News

Innovation / 17.05.2023
Reorganization in the Executive Board of Eckert & Ziegler

The Supervisory Board of Eckert & Ziegler AG has now formally approved the reorganization of the Executive Board already announced in December 2022. Accordingly, the founder and Chairman of the Executive Board, Dr. Andreas Eckert, and the Chief Operating Officer of the Medical segment, Dr. Lutz Helmke, will resign from their positions at the end of the Annual General Meeting on June 7, 2023, by mutual agreement. Their responsibilities and the chairmanship of the Executive Board will be taken over by the current Chief Sales Officer of the Medical segment, Dr. Harald Hasselmann. Newly appointed to the Executive Board and responsible for the Isotope Products segment will be Frank Yeager, the longtime head of this California based business unit. The positions of Dr. Hakim Bouterfa and Jutta Ludwig on the Management Board remain unaffected by the changes.

Andreas Eckert will later move into the Supervisory Board. His family office holds about one-third of the shares in Eckert & Ziegler AG and rights to appoint members of that body. Before moving to the Supervisory Board, he intends to finish a number of projects under the framework of a consulting agreement.

Lutz Helmke, who is leaving the Executive Board at his own request under an early retirement scheme, will, together with Harald Hasselmann, remain Managing Director of the subsidiary Eckert & Ziegler Radiopharma GmbH. He will focus on the development of actinium production in Dresden-Rossendorf.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 1.000 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
 

Source: Press Release EZAG
Reorganization in the Executive Board of Eckert & Ziegler

Innovation, Patient care / 08.05.2023
Recognized Australian Endocrine & Hypertension Center Joins International Groups with a Clinical Trial of PentixaPharm’s Primary Aldosteronism Lead Candidate

Following clinical investigations of hypertension specialists in the Netherlands, France, the United States, and China, the Monash Medical Center (Monash Health) and Hudson Institute in Melbourne, Australia, has commenced an investigator initiated clinical study with PentixaPharm’s novel lead compound [68Ga]Ga-PentixaFor targeting CXCR4 (international nonproprietary name Gallium (68Ga) boclatixafortide) for the imaging of aldosterone-producing adrenal adenomas. In collaboration with the Nuclear Medicine department at Monash Health and Melbourne’s Peter MacCallum Cancer Center, the study team recently treated six hypertensive patients to evaluate for a surgically curable form of primary aldosteronism.

Primary Aldosteronism (PA) refers to the hypersecretion of aldosterone, a hormone that increases blood pressure and consequently leads to high vascular morbidity including stroke and heart failure. The excess release of the hormone is often caused by overactive adrenal glands. If only one of the two human adrenal glands is affected (“unilateral aldosterone-producing adenoma” or “APA”), the patient can in many cases be cured. Surgeons just remove the affected adrenal gland. If both glands are affected (bilateral adrenal hyperplasia, BAH), this is not possible.

Finding out whether only one or both glands are affected, however, is difficult, because the diagnostic gold standard, adrenal vein sampling (AVS), is a labor intensive, expensive, and invasive surgical procedure. It also poses a high risk of failed or inconclusive results. For this reason, many APA patients remain undetected and hence undergo unnecessary and often harmful medication. The availability of an easy-to-use imaging compound that reliably identifies the APA-subtype in patients with aldosterone-mediated hypertension may be a game-changer in making treatment decisions for millions. It would most likely have a large impact on clinical practice and enable a large number of hypertension patients to be cured.

The aim of the Investigators in Melbourne is to use [68Ga]Ga-PentixaFor as novel non-invasive PET imaging compound to distinguish between the subtypes in patients with visible adrenal adenoma(s) on CT scans. Assoc. Prof. Jun Yang, coordinating Principal Investigator of the clinical study explains: “Whilst we are tempted to blame the aldosterone excess on visible adrenal adenoma(s), these adenomas could very well be non-functioning. The Gallium-68 based radio-diagnostic compound promises to radically improve patient management by replacing the invasive and difficult to perform adrenal vein sampling (AVS) in determining the functionality of these nodules. This is an exciting prospect. Monash Medical Center has therefore decided to recruit 20 PA patients to validate the utility of the compound.”

“The visualization of the adrenal gland tumors by [68Ga]Ga-PentixaFor will potentially improve the subtyping of PA and facilitate better treatment decisions. The study in Australia is in line with clinical activities in Europe and in the USA, which are supported by PentixaPharm. PET/CTs using [68Ga]Ga-PentixaFor might enable more PA patients to receive the right therapy”, comments Dr. Hakim Bouterfa, co-founder of PentixaPharm GmbH and Chief Medical Officer at Eckert & Ziegler AG.

Eckert & Ziegler (ISIN DE0005659700, TecDAX), the owner of the rights to the underlying [68Ga]Ga-PentixaFor PET compound, supports Monash Medical Center and other investigators worldwide by providing the diagnostic compound in exchange for access to clinical data.

[68Ga]Ga-PentixaFor is being developed by Eckert & Ziegler's subsidiary PentixaPharm GmbH also as a superiorly sensitive diagnostic for a portfolio of hematooncological malignancies. For more information visit www.pentixapharm.com

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with more than 1.000 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.

 

Research, Innovation, Patient care / 03.05.2023
Interview about Berlin-Buch – A Location for Future Innovation

Dr. Christina Quensel, CEO of the Campus Berlin-Buch GmbH
Dr. Christina Quensel, CEO of the Campus Berlin-Buch GmbH

The BerlinBioCube incubator is currently being built on Campus Berlin-Buch. The new five-story building provides a total of 8,000 m² of space for state-of-the-art laboratories, offices, and shared spaces. |transkript spoke to the Managing Director.
 

transkript. Construction sites are visible at biotech locations all over the country. In Berlin-Buch, more progress has been achieved. What is the current situation at your site?

Christina Quensel. The entire space in our existing buildings is already leased out. As early as 2016, we realized that we needed to expand. Technology transfer was also strengthened by Berlin’s major universities forming the Berlin University Alliance and the city’s non-university research institutions joining forces to create BR50. The Covid-19 pandemic made it clearer still that innovation from Germany can be successful – and needs space. Our principal shareholder, the Federal State of Berlin, was easily convinced. We were able to utilize the maximum building size on the construction site, and the opening is now scheduled for October 2023.

transkript. So you were very fortunate with the timing, given that demand is particularly strong in the region around the German capital, is it not?

Quensel. Yes, it was good that we got off to an early start. And we did not let up during the pandemic either. On the contrary, we had so many ideas in addition to the construction project that we needed to put a foot on the brake at times. But now we are delighted to be able to add space for a further 10 to 20 companies in one go. These will join the 50 life science firms and 70 consultants and service providers that are already based there.

transkript. How do you go about choosing your tenants? What criteria do you apply?

Quensel. They have to be companies that fit the profile of our campus and that in turn will benefit from the environment, their neighbors. Everything with a focus on health. We attach great importance to connectivity with others, whether in scientific or technological terms; it is important that new companies fit in, enabling them to make good use of the interactivity between enterprises and the scientific community, as well as to boost their own activities. In this context, we focus on personalized medicine in diagnostics and treatment.

transkript. Which companies might you like to mention briefly in this regard?

Quensel. They range from CELLphenomics, a company that takes patient tumor tissue in culture on which to test parallel treatment strategies with various compounds with a view to making recommendations for further treatment, to T-knife, which develops cell therapies in the field of personalized immuno-oncology. T-knife has been highly successful in acquiring international financial backers, with major rounds of financing, which of course has a positive knock-on effect for the entire campus. Everyone here can benefit from their experience. We also have on board Eckert & Ziegler, a key player in radiopharmaceuticals, and Ariceum, a brand new start-up in this field. We are also home to companies that innovate in RNA drugs and approaches, such as Silence Therapeutics and Pramomolecular.

transkript. Who will move into the new BioCube, how strong is the demand?

Quensel. The BioCube is a no-brainer, particularly because there are very few other places in Germany where a company can move in at such short notice. Opening in the fall gives us a major advantage. T-knife will lease large areas, but of course there is also sufficient space for smaller companies. As we all know, it’s the mix that matters. However, we have consciously opted against offering co-working in those labs, since most of the companies attach great importance to IP protection. But we do encourage co-working in our shared spaces, because we value inter-company communication. The BerlinBioCube has high amenity value and creates spaces with special offers that inspire people to get together.

transkript. How can you remain flexible with all that demand, or is your mantra to achieve full occupancy?

Quensel. We know from our long experience that not every company succeeds: we have repeatedly seen firms fold over the years. We experience fluctuations, which is why we always have an average vacancy rate of a few percent each year due to various ups and downs in the companies’ development. That gives us a certain amount of flexibility in the face of rising demand.

transkript. How else do you support the companies, besides providing them with space?

Quensel. We offer a whole range of professional development and networking opportunities, from seminars to summer parties. The “Talk in the Cube” series will enable enterprises to present themselves, and also to address the issues currently preying on the tenants’ minds. In this way, we want to build a bridge between science and business, and fill it with life, ensuring that translation is not just an empty word. Instead, the transfer of knowledge from person to person should also embrace the next generation of founders.

transkript. There are many different types of operations for a cluster organization. What is the situation with Campus Berlin-Buch?

Quensel. Our business is mainly to operate the BiotechPark. We currently see Campus Berlin-Buch in its entirety as one of the largest biotech innovation hubs in Germany, measured in terms of square meters, the number of companies served, and the number of employees. And of course we would like to maintain this position. Beyond these facts, we are developing many activities aimed at enhancing the attractiveness of the location. But it goes without saying that these activities must also recoup the costs incurred. One example is our staff health maintenance service. This may sound rather dry, but it has had an incredible impact and has now been a crucial element for years, involving all campus staff – not only those employed by the companies but also those working at the research institutes. People meet each other at CampusVital, do sports together, and make contacts easily beyond the boundaries of their campus facilities or enterprises. Excellent services and this kind of interaction are key factors for the stability and future development of companies on the campus.

transkript. How do you see the relationship with other sites in Berlin? Is it a never-ending competition?

Quensel. To be honest: This diversity is necessary. And we, the colleagues who operate the individual sites, are getting better and better at networking with each other. Berlin’s 11 “Zukunftsorte” (the places where tomorrow’s future is being created today) represent an important initiative that supports such networking and helps to overcome competitive instincts. After all, we can learn a lot from each other in terms of attracting and supporting young companies, as well as with regard to operational aspects, including energy efficiency, and other issues. We are keen to make it even easier to find each location’s individual offerings and, with the help of Berlin Partner, we will continue to expand cross-information and cross-networking. The good thing is that individual sites have developed their own distinct profile. Environmental technologies tend to be found in Adlershof, there is a Food Campus, a focus on Artificial Intelligence, and an array of other specializations.

transkript. Just how cooperative is it?

Quensel. Many of Berlin’s biotech/life science players meet regularly, and we have developed a good level of collaboration. In this context, continuous mutual learning is paramount, as well as how we can better pool resources, which are limited for all of us. As far as services for such things as start-up consulting are concerned, it would be nice if they could be used by scientists from all institutions, whether from Berlin-Mitte, Berlin-Buch or Potsdam, whether from a university, a university of applied sciences, or a non-university institution.

transkript. Is Berlin now truly coming up trumps?

Quensel. We are simply delighted to receive so many requests. With an even greater international scope, the BioCube will also be a welcome pick-me-up for the long-established institutions.

 

Published in Magazin |transkript 2.2023 I Spezial. Manufacturing/Tech Parks

 

Find out more about the BerlinBioCube: www.berlinbiocube.de

Find out more about Campus Berlin-Buch: www.campusberlinbuch.de

 

Innovation / 20.04.2023
Eckert & Ziegler Receives Manufacturing Authorization for GMP-grade Lutetium-177

Eckert & Ziegler Radiopharma GmbH, a subsidiary of Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, TecDAX), has received the manufacturing authorization for Lutetium-177 (non-carrier-added Lu-177) in GMP grade from the competent German authority. The approval is the basis for the marketing authorization of Lutetium-177 as a drug, but also for use of this radioisotope as a starting material for the manufacture of radiopharmaceuticals. By making Lutetium available to a significantly broader range of users, the approval will enable Eckert & Ziegler to further continue its successful strategy as one of the world leading isotope suppliers.

Lutetium-177 based radiopharmaceuticals are well established for the treatment of neuroendocrine tumors and prostate cancer. Numerous other radiotherapeutics for various cancer types are currently under development and evaluated in clinical trials, which is why experts expect a strong increase in demand for the radioisotope.

“Following our recent DMF submission in the USA, this approval is another indispensable component to further expand the supply of Lutetium-177 to pharmaceutical companies and customers around the world,” explained Dr. Lutz Helmke, member of the Executive Board and responsible for the Medical segment at Eckert & Ziegler. “We will not only meet the increasing demand in general, but also use the radioisotope for contract development and manufacturing activities that we are setting up for partners in our facilities in Europe, North America and Asia."

The beta emitting Lutetium-177 is linked to a tumor specific ligand which then targets the tumor cells to destroy them. A major advantage of Lutetium based drugs is that they are used in a theranostic approach. The same ligand of the radiotherapeutic will be linked to a diagnostic radioisotope such as Gallium-68. With the help of so-called PET scanners, the patient's response rate and thus the benefit of a treatment can be predicted in advance with high precision.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with nearly 1,000 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Contributing to saving lives.

www.ezag.com

Innovation / 19.04.2023
Ariceum Therapeutics Announces Extension of Series A Financing to EUR 47.75M to Advance its Next Generation Radiopharmaceutical Clinical Pipeline

  • New investors, Andera Partners and Earlybird Venture Capital, join existing investor, Pureos Bioventures raising an additional EUR 22.75 million
  • Funds will be used to advance clinical pipeline and further build Ariceum Therapeutics
  • Olivier Litzka from Andera Partners and Christoph Massner from Earlybird Venture Capital to join the Ariceum non-executive Board of Directors 

Berlin, Germany, 18 April 2023 – Ariceum Therapeutics (Ariceum), a private biotech company developing radiopharmaceutical products for the diagnosis and treatment of certain hard-to-treat cancers, today announces the successful completion of a Series A extension financing, raising a further EUR 22.75 million, following the EUR 25 million Series A financing announced in June 2022. The financing was co-led by new investors Andera Partners and Earlybird Venture Capital, with participation from existing investor Pureos Bioventures, now doubling its original investment in the Company.  As part of the investment, Olivier Litzka, Partner at Andera Partners, and Christoph Massner, Principal at Earlybird, will join the Ariceum Board of Directors.

Ariceum intends to use the proceeds from the financing to advance its clinical pipeline and to further build the Company focusing on its lead asset and proprietary peptide derivative, Satoreotide, as well as building a pipeline of further projects.

Satoreotide is a radiopharmaceutical drug and an antagonist of the somatostatin type 2 (SST2) receptor which is overexpressed in many cancers, including certain neuroendocrine and other aggressive, hard-to-treat cancers with poor prognoses such as small cell lung cancer (SCLC). Ariceum aims to use satoreotide as a ‘theranostic’ for both the diagnosis and treatment of tumours expressing the SST2 receptor. Satoreotide is in early clinical development and, as of today, has been administered to more than 100 patients including more than 150 therapeutic administrations in different indications.

Manfred Rüdiger, PhD, Chief Executive Officer of Ariceum Therapeutics, said: “As we continue to make promising progress at Ariceum, the new funds will allow us to advance our clinical pipeline of diagnosis, monitoring and precision treatments to improve the lives of those facing very challenging cancers. The additional investment is a strong endorsement of our targeted radiotherapy product and reflects the opportunity that radiopharmaceutical drugs offer in visualizing and treating cancer. We are very pleased to welcome both Andera Partners and Earlybird Venture Capital to our investment syndicate and would like to thank our existing investors for their continued support.”

Olivier Litzka, PhD, Partner of Andera Partners, remarked: “At Andera we have been following the radiopharmaceuticals space for some time, looking for an opportunity to support a compelling project. As a result, we are now very happy to be able to back the talented and experienced team of Ariceum with a first clinical project centered around a meaningful disease application in Small Cell Lung Cancer. It is great to support the company in its bold ambition to build a pipeline of radiopharma projects through deals and partnerships. We are also joining an already powerful board of experts and strong European VCs. Altogether, we believe these are solid grounds to build a leading biotech company in the radiopharmaceuticals field.”

Christoph Massner, PhD, Principal of Earlybird Venture Capital, commented: “We are delighted to support Ariceum as it advances its proprietary clinical programs to address aggressive cancers with a poor prognosis. Earlybird is especially excited about Ariceum’s ability to stratify patients for treatment via its theranostics approach. This will provide the best possible patient outcomes and attractive health economics. I look forward to working with Ariceum’s experienced management team and strong investor base as it enters its next development stage.”

ENDS

ariceum-therapeutics.com

Innovation / 14.04.2023
CELLphenomics’ and KYAN Therapeutics combined platforms provide best-in-class solutions to support the biopharma industry

Berlin/Singapore (April 14, 2023)

CELLphenomics and KYAN Therapeutics announced their new partnership today. By combining KYAN's technology platform, Optim.AI™ - which utilizes artificial intelligence to predict the effects of drug combinations and CELLphenomics' proprietary PD3D® technology, this partnership aims to offer an efficient approach to expedite drug development process in the biopharmaceutical industry. The combination of these two unique technologies will allow reliable conclusions about the treatability of the tumor and its functional causes of therapeutic success and/or failure, leading to novel treatment combinations and faster preclinical development of new anti-cancer drugs.

KYAN’s technology platform, Optim.AI™, combined with CELLphenomics’ expertise in PD3D® model establishment and cultivation of patient-derived complex cell culture model cultures from various tumor entities and toxicity testing support clinical compound selection through the testing of:

  • drug efficacy
  • off-target toxicity
  • combination strategies
  • mode of action
  • biomarker identification
  • patient stratification
     

Optim.AI™ is a revolutionary technology that combines small data AI and wet lab biology. KYAN's platform solves large and complex search spaces to identify and rank combination treatments with small amounts of tissue sample. “The main breakthrough for KYAN is that we only need to use minimal amounts of data points to predict and solve for large search spaces. The data points that we generate are from prospective experiments that measure the phenotypic response of drugdose combinations across different biological models, like the PD3D® models established by CELLphenomics.“ said Hugo Saavedra, CEO of Kyan.

“CELLphenomics' patient-derived 3D cell culture models (PD3D®) recapitulate the tissue architecture of the original tumor and maintain key features of the donor tumor: IHC markers, genomic features, and key mutations,” said Dr. Christian Regenbrecht, cancer researcher and CEO of CELLphenomics. “They are highly predictive to treatment response and enable the biopharma industry to save time and laboratory animals.”

The development of new drugs and therapies for cancer patients requires a variety of preclinical studies to assess their safety and effectiveness, and previously included wide use of animal testing.  However, recent changes in regulations by US and European legislators have allowed applicants to use alternative methods for toxicity testing in biosimilar applications. This milestone was made possible by the introduction of highly reliable and predictive preclinical models such as our PD3D® platform. The FDA and EMA are in the process of adapting their guidelines accordingly. In this context PD3D® models will be a cornerstone of these new policies.

Please feel free to schedule your appointment with Dr. Christian Regenbrecht and Hugo Saavedra at the Annual Meeting of the AACR 2023 in Orlando, Florida.

Dr. Christian Regenbrecht, CEO of CELLphenomics: christian.regenbrecht@cellphenomics.com

Hugo Saavedra, CEO of Kyan: hugo@kyantherapeutics.com
 

CELLphenomics

CELLphenomics GmbH is a German biotech company founded in 2014. Our core competence is the establishment and cultivation of complex patient-derived cell culture models (PD3D®) from various solid tumor tissues and their application in research and drug development. Our PD3D® models robustly recapitulate the biological properties of the donor tissue and offer high-throughput efficacy testing, drug combination screening, toxicity profiling, target validation, drug sensitivity correlation with clinical response, and biomarker identification. Our continuously growing biobank comprises more than 450 organoid models from more than 20 tumor entities and is complemented by clinical and molecular data to support multiple research interests.

For more details, please visit: www.cellphenomics.com
 

KYAN Therapeutics

KYAN Therapeutics is a biotechnology company that tackles the complexity of cancer by combining small data AI and biological experiments. Our technology platforms were developed in collaboration with the University of California, Los Angeles (UCLA) and the National University of Singapore (NUS) to redefine how therapies are developed and offered to patients. From drug development to personalized medicine, KYAN offers an efficient solution to identify the optimal outcome to millions of possible drug-dose combinations. KYAN’s technology has been peer reviewed in several reputable and high impact factor journals and implemented in multiple clinical studies. For more details, please visit: www.kyantherapeutics.com

Source: www.cellphenomics.com

Innovation / 12.04.2023
Eckert & Ziegler Receives Environmental Approval for Jintan Radioisotope Site

Eckert & Ziegler’s fully owned subsidiary Qi Kang Medical Technology Ltd. (QKM) has recently received the authorization for its Environmental Impact Assessment (EIA) from the Department of Ecology and Environment of Jiangsu Province in China. The responsible authorities approved QKM’s planned construction of a radioisotope production facility consisting of clean rooms for sealed and non-sealed radioactive material, laboratories for quality control and microbiology. The ratified EIA also includes the installation of a cyclotron with a maximum proton energy of 30MeV.

“The endorsement of the EIA shows the support of the local authorities and is an important prerequisite for the site approval”, explains Jutta Ludwig, Executive Director responsible for the Asia Business. “We will now focus on the next steps in the regulatory process and continue the construction. When completed, the Jintan facility will be able to meet the radiopharmaceutical demands of the growing regional Asian markets and serve as a back-up for the production sites that Eckert & Ziegler already operates in Europe, North and South America”.

Experts expect that the emergence of highly effective cancer radiotherapeutics for neuroendocrine tumors, prostate cancer and further radiopharmaceuticals currently under development will significantly increase demand for the radioisotopes Yttrium-90, Lutetium-177 and Gallium-68 in China and globally. With the plant in Jintan, Eckert & Ziegler will increase its total production capacity and thus consolidate its position as the world's leading manufacturer of radioactive pharmaceutical agents.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with nearly 1,000 employees is a leading specialist for isotope-related components in nuclear medicine and radiation therapy. The company offers a broad range of services and products for the radiopharmaceutical industry, from early development work to contract manufacturing and distribution. Eckert & Ziegler shares (ISIN DE0005659700) are listed in the TecDAX index of Deutsche Börse.
Contributing to saving lives.

Research, Innovation / 28.03.2023
Supporting innovation in biomedicine

Dr. Daniel Romaker, Dr. Beatrice Pöschel, Dr. Antonia Klein and Dr. Gerd Müller of the Technology Transfer Office (© Felix Petermann, Max Delbrück Cente
Dr. Daniel Romaker, Dr. Beatrice Pöschel, Dr. Antonia Klein and Dr. Gerd Müller of the Technology Transfer Office (© Felix Petermann, Max Delbrück Cente

The Max Delbrück Center wants to shape the future of medicine through innovation. But turning basic research into marketable products requires gaps to be bridged. This is achieved by the Technology Transfer Office – through funding schemes such as BOOST and Pre-GoBio. The winning projects for 2023 have now been selected.

It is not unusual for ten years or more to pass before scientific discoveries become marketable products that are used in patient care. The Max Delbrück Center’s Technology Transfer Office guides scientists down the long and winding road toward licensing agreements, industrial collaborations, and start-up formation, often helping them take critical steps toward marketability. The team of six organizes seminars on product development and patenting strategies, provides coaching and mentoring, helps find industry partners and funding opportunities, and takes the lead on patent and licensing administration. It works closely with the Technology Transfer Office of Charité – Universitätsmedizin Berlin and with Ascenion GmbH, an independent knowledge and technology transfer company.  

The offerings of the Technology Transfer Office include two funding schemes. “Our BOOST scheme is an ideas competition with which we support early-stage projects,” explains Innovation and Technology Manager Dr. Daniel Romaker. Applications are open to Max Delbrück Center scientists whose ideas are still in the embryonic stage or require a proof of concept or feasibility study. The winners of the competition receive start-up funding of €40,000 over twelve months for materials and contracts. In addition, an external coach gives guidance on how to make product development more targeted. 

This year’s BOOST grants go to three researchers: Dr. Altuna Akalin, who leads the Bioinformatics and Omics Data Science Platform; Dr. Zsuzsanna Izsvák, who leads the Mobile DNA Lab; and Professor Kathrin de la Rosa, who leads the Cancer & Immunology/Immune Mechanisms and Human Antibodies Lab and who is working with her PhD student Clara Vázquez García to create a new vaccine development platform. Unfortunately, we cannot yet publicly reveal anything else about this project. The other two winning projects are presented here:

Dr. Altuna Akalin: Captain Kirk now uses ChatGPT

Even Captain Kirk spoke to the Starship Enterprise’s on-board computer when he wanted to know the coordinates of a star system or some other computation. Akalin now wants to make voice-controlled communication with computers possible for scientists as well. Based on GPT technology, he intends to develop a text-based dialogue system that serves as a user interface for analysis programs. GPT, which stands for “Generative Pre-trained Transformer,” is a state-of-the-art machine learning technology for large language models. “Programs for analyzing sequencing data are not very user-friendly,” the data scientist explains. “They tend to be difficult to use if you don’t have a computer science background.” He wants to create a chatbot that communicates with researchers, asking them such things as what samples are available and what exactly needs to be analyzed. The chatbot will guide them step by step through data analysis, and will also be linked to an open-ended data analysis tool. After the chatbot converts the researchers’ input into computer code, the program starts its calculations and once finished the system delivers the results. “Scientific research generates so much data that there simply aren’t enough bioinformaticians to analyze it all,” says Akalin. “The system is designed to enable researchers to analyze their own data. And it should allow bioinformaticians to perform multiple analyses simultaneously, making them more efficient.”

Dr. Zsuzsanna Izsvák: Steering genes into a safe harbor

Izsvák invented the Sleeping Beauty technology in the late 1990s, and now wants to develop the tool further. Sleeping Beauty is an artificial transposon, a jumping gene that can change its position in the genome. Its ability to integrate into the genome can not only be used in gene transfer, such as to transfer a therapeutic gene into patient cells for gene therapies, but also in immunotherapies against cancer that work by boosting a patient’s own immune cells with an artificial receptor (known as a chimeric antigen receptor, CAR) so that they can better detect and fight tumor cells. Izsvák is also working on using Sleeping Beauty to treat age-related macular degeneration. A clinical trial testing this therapy is expected to begin later this year.  
 
“The Sleeping Beauty transposon system can be used to insert DNA snippets into cellular DNA and is cheaper to produce than viral gene shuttles,” says Izsvák. “Plus, it’s safer and easier to handle, making it a real competitor to viral vectors.” In the BOOST project, the researcher wants to focus on making gene transfer safer. She is therefore looking for regions in the genome that are suitable for therapeutic gene insertion. In such a “safe harbor,” no other activities should be taking place to ensure that the host genes are not disrupted and that the therapeutic gene is well expressed. “This is a real challenge,” says the researcher. “Promoters, which are DNA sequences that regulate gene expression, are used to achieve good expression. These can overload the system, trigger stress responses, and completely change the cell’s transcriptome – a real biosafety concern.” To get around this problem, the researcher wants to create a sort of navigation aid that will help Sleeping Beauty reach a “safe harbor.” 

Making the leap from lab to clinic

With its second funding scheme, Pre-GoBio, the Max Delbrück Center supports projects that have the potential to make the leap from the lab to the clinic. “Our basic researchers want to gain insights into the molecular mechanisms of health and disease,” says Romaker. “They don’t necessarily have a specific application in mind, but the overall goal of research at the Max Delbrück Center is to develop drugs and technologies that can help patients.” So the innovation and technology managers are on the lookout for projects that have a certain inherent value in the marketplace. “These are research findings that could help meet a medical need by offering, for example, the prospect of new therapeutic options for diseases that are currently untreatable or difficult to treat,” explains Romaker.  

As with BOOST grants, the decision on who receives Pre-GoBio funding is made by a panel of experts to whom the applicants must make their research palatable through short talks. The panel then selects two projects that each receive €450,000 for up to three years. At the end of 18 months, the progress of the project is assessed to determine whether to continue with third-year funding. A workshop is held at the very end to evaluate the results of the entire project; a further €150,000 of funding may then be provided for an additional year. Two projects have been chosen for 2023: the first is led by Professor Markus Landthaler, head of the RNA Biology and Posttranscriptional Regulation Lab; and the second by Professor Gary Lewin, head of the Molecular Physiology of Somatic Sensation Lab. 

Professor Markus Landthaler: The protein booster

Biopharmaceuticals, also known as biologics, are biotechnologically produced drugs that can be used to treat serious diseases like cancer, rheumatism, and multiple sclerosis. Their production is very complex, as they are often made from genetically engineered mammalian cells. Among the most commonly used host cell systems are Chinese hamster ovary (CHO) cells, which are an immortalized cell line derived from the ovaries of the Chinese hamster. 

“CHO cells have become a preferred choice for therapeutic protein production because they can be grown in large-scale, high-density cell cultures and can be genetically engineered relatively easily,” explains Landthaler. “They produce proteins reliably and effectively while remaining stable.” However, the process is extremely time- and labor-intensive. Landthaler had an idea for how to boost the production of these biologics. “We succeeded in engineering the CHO cells so that they can produce more proteins of therapeutic interest,” he says. To do this, the scientists made sure that a certain protein was expressed in the CHO cells, which in turn caused an increase in the production of the desired therapeutic proteins. 

“This project is a prime example of successful institutional funding,” says Romaker. Landthaler used a BOOST grant to begin the first trials; a successful method for reprogramming the CHO cells was patented last year; and the Pre-GoBio funding is now helping to put the finishing touches on the technology. “If everything works as planned, the production capacity of CHO cells will be increased many times over,” says Romaker. “That would catapult biologic drug production to a whole new level. The pharmaceutical industry has been waiting for this for a long time.” In addition to the financial support from Pre-GoBio, Landthaler has been awarded a grant from the Helmholtz Initiative and Networking Fund that will enable him to test everything under industrial conditions and show that the method is also suitable for producing antibodies. 

Professor Gary Lewin turns off the pain

Ion channels are proteins that form pores in the cell membranes through which electrically charged particles can pass. That’s why they are also called channel proteins. While studying melanoma cells, Lewin’s team discovered a previously unknown ion channel. In experiments with mouse models, two of the team members – Dr. Sampurna Chakrabarti and Dr. Alice Rossi – were able to show that this ion channel is largely responsible for the sensitivity of tactile and pain receptors. Together, they submitted the application for the project. “That means if we succeed in blocking this ion channel, we could help patients who suffer from chronic pain,” says Lewin. His team therefore plans to screen drugs in the hope of finding a molecule that turns off the ion channel and thus alleviates pain.

Networking, with or without pizza 

The Technology Transfer Office not only provides scientists with guidance, advice, and funding – it also promotes networking and exchange among the Center’s researchers. A good example are the monthly “meet-and-eat” sessions that it organizes. “Before the coronavirus pandemic, we used to meet in person for pizza and networking,” Romaker’s colleague Dr. Antonia Klein recounts. “But at the moment, we’re still holding virtual meetings.” The scientists have to get the pizza themselves – but more people can take part.  

Text: Jana Ehrhardt-Joswig 

 

Research / 16.03.2023
Novel disease models for multiple myeloma

© AG Janz, Max Delbrück Center
© AG Janz, Max Delbrück Center

A team of scientists led by Martin Janz and Klaus Rajewsky at the Max Delbrück Center has successfully generated genetically defined mouse models for two subtypes of multiple myeloma. These models will contribute to a better understanding of how the disease develops in humans. The team has now published their findings in the journal PNAS.

B lymphocytes – also known simply as B cells – play a central role in the immune system. If pathogens enter the body, B cells are activated and develop into plasma cells, which then release antibodies. One important step in this process is the germinal center reaction. If the B cells’ maturation into plasma cells is disrupted, multiple myeloma can develop – one of the most common blood cancers. This disease has a variety of subtypes and is not yet curable.

Multiple myelomas develop very slowly and in several stages. The process is initiated by spontaneous genetic aberrations that occur during the germinal center reaction and influence the process of B-cell maturation. The preliminary stage of the disease is called monoclonal gammopathy of undetermined significance (MGUS) – a benign precursor that causes no symptoms. The only biomarker is an increased concentration of the antibody secreted by the plasma cells in the blood. It takes further genetic changes in the plasma cells for the line between MGUS and malignant cancer to be irreversibly crossed.

Models exactly mimic the human disease

Previous mouse models have not been able to accurately represent the different genetic subtypes of myeloma. A team led jointly by renowned B-cell researcher Professor Klaus Rajewsky and lymphoma expert Dr. Martin Janz has now succeeded in doing just that. In the journal PNAS, they present novel mouse models that precisely replicate two subtypes of human multiple myeloma. “We have also been able to show that the interaction of several genetic aberrations is a decisive factor in the development of the disease,” says Janz, head of the Biology of Malignant Lymphomas Lab at the Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center and Charité – Universitätsmedizin Berlin.

The researchers started by establishing three different groups of transgenic mice, each carrying just one genetic modification – an extra copy of the genes that encode either cyclin D1, MMSET, or Ikk2. Cyclin D1 regulates cell cycle progression, and the incorrect activation of its encoding gene due to an aberration promotes increased cell division. MMSET is a histone methyltansferase that regulates the accessibility of DNA. Overexpression of its encoding gene profoundly changes the epigenetic pattern of the cell and enhances its susceptibility to undergo malignant transformation. Ikk2 activates a component of the NF-κB signaling pathway, which plays an important role in cell growth and immune response. The frequent activation of this signaling chain is a distinguishing characteristic of multiple myeloma.

Multiple myeloma mostly occurs in old age

In a second step, the scientists crossed the cyclin D1 and MMSET mice with Ikk2 mice and selected the offspring with the desired genetic attributes – i.e., cyclin D1 + Ikk2 and MMSET + Ikk2. They then mated these with another mouse strain, which allowed the modified genetic information to be activated only in the B cells and only as part of the germinal center reaction. “It was striking to see how the primary modification in the mouse model – through overexpression of either cyclin D1 or MMSET – really shapes the profile of the disease subtype,” says Rajewsky.

It took 70 to 90 weeks for the experimental mice to develop full-blown multiple myeloma – a long time in the life of a mouse. Though this timeline complicates the experiments, it does accurately mimic the development of the disease in humans: for us, too, multiple myeloma tends to emerge later in life and often takes years to progress to the malignant stage. It is estimated that up to five percent of all people over the age of seventy have the benign precursor MGUS. “Our models make it clear that multiple myeloma only develops when several genetic aberrations occur together,” Janz explains. “Mice that were only transgenic with regard to cyclin D1 or MMSET and did not also carry modified Ikk2 did not develop the disease.”

An important starting point for further tests

Although the symptoms are similar – elevated calcium levels, anemia, fatigue, increased susceptibility to infection, renal insufficiency, bone damage – multiple myeloma subtypes in humans differ with regard to the nature of the genetic changes, gene expression profiles, and prognosis. “Our models provide an important foundation for investigating the differences and similarities between the various subgroups and will help us to develop more specific, individualized therapeutic strategies in the long term,” says Dr. Wiebke Winkler, the study’s lead author.

The researchers now want to use the novel mouse models to identify the subgroups’ “genetic Achilles heels,” as Janz puts it. In addition, they want to activate the B cells in the animal models in an even more targeted way and to introduce more secondary genetic modifications in the mouse genome. “After all, Ikk2 is not the only driver of the disease,” stresses Janz.

Text: Catarina Pietschmann

Figure: Left: Normal bone marrow in the control animals with stained myeloid cells. Right: Bone marrow in the transgenic animals with plasma cell infiltration. © AG Janz, Max Delbrück Center

Source: Press Release Max Delbrück Center
Novel disease models for multiple myeloma

 

Innovation / 03.03.2023
Eckert & Ziegler Submits Drug Master File for Lu-177 n.c.a.

Eckert & Ziegler (ISIN DE0005659700, SDAX) has successfully submitted a Type II Drug Master File (DMF) with the U.S. Food and Drug Administration for lutetium (177Lu) chloride solution (containing no-carrier-added radioisotope Lutetium-177), an active pharmaceutical ingredient and received DMF registration number 038043.

Drug manufacturers can now refer to this DMF when developing new radiopharmaceuticals for the U.S. market and use the lutetium (177Lu) chloride solution in clinical trials of drugs, for example. A large number of tumor-specific drugs can be labeled with the beta emitter lutetium-177, which brings the radiating effect of the isotope directly to the tumor cell.

"We are excited about the access to the U.S. market for lutetium-177 based radiotherapeutics," explains Dr. Lutz Helmke, member of the Executive Board and responsible for the Medical segment at Eckert & Ziegler. "Thanks to our joint venture with Atom Mines LLC, we have excellent access to the scarce and indispensable precursor ytterbium-176 and thus the possibility to supply no-carrier-added lutetium-177 in highest purity and reliably to pharmaceutical customers worldwide."

Radionuclide therapy with lutetium-177, is becoming well established as a valuable treatment option within precision oncology for various indications. Eckert & Ziegler is one of the leading partners for the radiopharmaceutical industry, offering complete early development services in addition to the supply of isotopes, including process development and scale-up, CMC development, manufacturing and packaging, product release and stability programs.

About Eckert & Ziegler.
Eckert & Ziegler Strahlen- und Medizintechnik AG with nearly 1.000 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.
Contributing to saving lives.

www.ezag.com

Research / 23.02.2023
The harmful effects of immune cells in hypertension

Copyright: Maria P. Kotini, University of Basel
Copyright: Maria P. Kotini, University of Basel

Hypertension can damage the heart, brain, and blood vessels. The immune system plays an important role in this process, Suphansa Sawamiphak from the Max Delbrück Center reports in Cardiovascular Research. The study, using zebrafish, found that inflammation causes macrophages to damage blood vessels instead of protecting them.

Hypertension, or high blood pressure, tops the list of chronic health conditions. It affects about one-third of the world’s population, including nearly 44 percent of German citizens. If the pressure in the blood vessels is too high, the body’s organs – mainly the brain, the heart, and the blood vessels – suffer as a result. The consequences go beyond an increased risk of developing serious cardiovascular diseases like strokes or heart attacks. In a healthy body, the heart, brain, and blood vessels also play a key role in regulating blood pressure. If they are damaged by persistently high blood pressure, this regulatory ability is lost – creating a vicious circle.

To lower blood pressure, patients should make changes to their lifestyle, such as eating a well-balanced, low-salt diet, exercising regularly, and stopping smoking. Some drugs, like beta blockers and ACE inhibitors, can also help: “Conventional medications can lower blood pressure, but they fail to achieve the desired protective effect on the organs in a large portion of patients,” says Dr. Suphansa Sawamiphak, who heads the Cardiovascular-Hematopoietic Interaction Lab at the Max Delbrück Center. This is particularly evident, she says, in the brain, where hypertension causes tiny blood vessels to become permeable, or eventually die off, adding: “This means there must be other control centers in the overall process that we can’t target with conventional therapeutic agents.”

Researchers have known for some time that components of the immune system may play a role here. Inflammatory responses in the body contribute to high blood pressure and have harmful effects on organs, but it is not yet known exactly how this occurs.

Immune cells damage blood vessels in the zebrafish brain

So Sawamiphak and her team at the Max Delbrück Center and collaborators working in Italy and Switzerland, studied larval zebrafish to shed more light on the underlying biological mechanisms. “This is an excellent model system for investigating many questions, since it is easy to manipulate the organisms by changing the environment,” explains the biologist, adding: “Because young zebrafish are transparent, we can literally see how this affects the living fish.”

To analyze the role of the immune system in hypertension, the research team raised zebrafish larvae in water with low ion concentration. This creates an ion imbalance in their bodies that is comparable to excessive salt consumption in humans, thus leading to high blood pressure. The team then examined how this affects the blood vessels in the brain.

According to the researchers’ observations, hypertension causes an increase in both the number of macrophages and microglia – special immune cells of the brain – that can get in touch with the vascular surface. There, they come into contact with the endothelium, the innermost cellular layer of blood vessels, and progressively weaken the vessel walls. Damage is also done to the blood-brain barrier, which prevents harmful substances and pathogens in the blood from reaching the brain. “The interesting thing is that when blood pressure levels are healthy, macrophages and microglia normally help protect the vessels,” says Sawamiphak. “Our findings suggest that macrophages and microglia undergo extensive reprogramming during hypertension.”

Blocking signaling molecules prevents organ damage

An important role is played by inflammatory messengers like interferon gamma, which are released at a higher rate under hypertensive conditions. To experimentally substantiate this connection, they switched off the gene for a receptor to which interferon gamma normally binds. In these fish, hypertension did not cause any damage to blood vessels or to the blood-brain barrier. The team also succeeded in demonstrating in mice that therapeutic agents that inhibit interferon gamma can prevent common side effects of hypertension – including damage to the blood-brain barrier, degradation of blood vessels in the brain, and cognitive deficits.

“Our findings provide a completely new perspective on the role of inflammatory processes in the progression of hypertension,” says Sawamiphak, explaining the significance of her work. Now, she says, it is necessary to more precisely characterize the immune cells and immunomodulators involved in such processes and to verify their role in higher animals including humans. If this can be confirmed, it would mean that the team had uncovered new therapeutic targets for hypertension through this study. This would particularly benefit patients for whom conventional drugs have failed to protect against progressive organ damage.

Text: Stefanie Reinberger

Source: Press Release Max Delbrück Center
The harmful effects of immune cells in hypertension

Research / 22.02.2023
Construction begins on new Imaging Innovation Center

The new building is being constructed in the vicinity of the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (Foto: Max Delbrück Center)
The new building is being constructed in the vicinity of the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (Foto: Max Delbrück Center)

They say Berlin is a constant building site – and it seems Campus Berlin-Buch is no exception. A new foundation pit is currently being excavated for construction of the Max Delbrück Center’s Imaging Innovation Center, which is scheduled to open in 2025.

Since January 16 of this year, the low and steady rumble of construction vehicles has been emanating from the north end of Campus Berlin-Buch. Workers are in the process of digging a new foundation pit in front of the building for cryo-electron microscopy (cryo-EM), in between Building 87 and the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP). In two years’ time, this site will be home to the Max Delbrück Center’s Imaging Innovation Center (IIC) – previously known by its working title, the Optical Imaging Center. Here, technology platforms and research labs working in the field of microscopy will be brought together under one roof.

“The IIC will be a place where researchers further develop microscopy technologies and image analysis methods to help them find answers to their biomedical questions – and make these technologies and methods available to other scientists,” says Dr. Jutta Steinkötter, who heads the Scientific Infrastructure Department. “As part of the Max Delbrück Center’s last scientific evaluation in 2012, it was recommended that the Center position itself even more broadly in terms of advancing microscopy imaging,” she explains, adding: “We now want to implement this recommendation.” The Max Delbrück Center already has plenty to show for its efforts to push the envelope in microscopy: In 2008, the Advanced Light Microscopy Platform was launched, headed by Dr. Anje Sporbert, which is now used by two-thirds of the Center’s researchers as well as external project partners. In addition, the Max Delbrück Center has expanded its collaborations in electron microscopy with the FMP, and now operates the Cryo-EM Platform in cooperation with Charité – Universitätsmedizin Berlin and the FMP. The Image Data Analysis Platform, headed by Deborah Schmidt, is one of three service units of the Helmholtz Imaging initiative, where researchers across the Helmholtz Association can receive free support with imaging-related matters and can network with each other. Last but not least, Dr. Andrew Woehler has set up the Systems Biology Imaging Platform at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB). These platforms are all rich sources of data that have already made a substantial contribution to numerous MDC publications through their methods, analyses and results.

Expanding the use of high-resolution microscopy in research

The IIC will bring together physicists, biophysicists, life scientists and bioinformaticians. In addition to the teams of the Advanced Light Microscopy Platform, the Cryo-EM Platform, and the Image Data Analysis Platform, other research groups will also move into the building – exactly which ones will be decided by a scientific committee. Together, they will develop new microscopy technologies and make them available for wider biomedical research. Of particular interest to the Max Delbrück Center research groups will be methods with high temporal and spatial resolution, imaging techniques for individual molecules, and correlative methods.

But there is still a lot of earth to be moved on campus before that point is reached. A truck garage and a long workshed previously stood on the site of the new foundation pit, and old electrical cables, heating and cooling pipes are still hidden in the ground. The excavators have also unearthed building rubble containing asbestos and other pollutants, which is causing delays to the planned schedule. “The disposal of such materials is strictly regulated,” explains project manager Karsten Hönig, an architect in the Technical Facility Management Department. “We have to collect samples and have them analyzed, which makes everything take a little longer.” The contract for construction of the building’s shell is currently being finalized and eleven companies have submitted bids – which, according to Hönig, is a lot: “The housing market crisis is working in our favor, but inflation is also affecting construction costs.”

Architectural firm Heinle Wischer is responsible for the design of the future IIC. The company has already realized several projects on Campus Berlin-Buch: the Max Delbrück Communications Center (MDC.C), the Research Institutes for Experimental Medicine (FEM), the FMP, and the cryo-EM building. The first master plan for the campus itself was also penned by Heinle Wischer. Like the cryo-EM building, the IIC will be built on a thick foundation slab designed to cancel out vibrations. Together with a vibration-resistant support structure, this will protect the sensitive microscopes from the regular ground tremors of the city. Meanwhile, a high-precision ventilation system will ensure a stable temperature and constant humidity in the microscopy labs.

The foundation stone is expected to be laid in the first half of 2023.

Text: Jana Ehrhardt-Joswig

News on the website of the Max Delbrück Center:
https://www.mdc-berlin.de/news/news/construction-begins-new-imaging-innovation-center

Research / 18.02.2023
Evolution: Miniproteins appeared “from nowhere”

© Clara-Louisa Sandmann, Max Delbrück Center
© Clara-Louisa Sandmann, Max Delbrück Center

Evolutionarily young miniproteins are unique in humans, and researchers have recently discovered thousands of them. Writing in Molecular Cell, Norbert Hübner and colleagues from the BIH and other institutions describe the origins of these tiny proteins and explain that they probably influence important cellular processes.

Every biologist knows that small structures can sometimes have a big impact: Millions of signaling molecules, hormones, and other biomolecules are bustling around in our cells and tissues, playing a leading role in many of the key processes occurring in our bodies. Yet despite this knowledge, biologists and physicians long ignored a particular class of proteins – their assumption being that because the proteins were so small and only found in primates, they were insignificant and functionless. The discoveries made by Professor Norbert Hübner at the Max Delbrück Center and Dr. Sebastiaan van Heesch at the Princess Máxima Center for Pediatric Oncology in the Netherlands changed this view a few years ago: “We were the first to prove the existence of thousands of new microproteins in human organs,” says Hübner. 

In a new paper published in Molecular Cell, the team led by Hübner and van Heesch now describe how they systematically studied these miniproteins, and what they learned from them: “We were able to show which genome sequences the proteins are encoded in, and when DNA mutations occurred in their evolution,” explains Dr. Jorge Ruiz-Orera, an evolutionary biologist in Hübner’s lab and one of the paper’s three lead authors, who work at the Max Delbrück Center and the German Center for Cardiovascular Research (DZHK). 

Ruiz-Orera’s bioinformatic gene analyses revealed that most human microproteins developed millions of years later in the evolutionary process than the larger proteins currently known to scientists. 

Yet the huge age gap doesn’t appear to prevent the proteins from “talking” to each other. “Our lab experiments showed that the young and old proteins can bind to each other – and in doing so possibly influence each other,” says lead author Dr. Jana Schulz, a researcher in Hübner’s team and at the DZHK. She therefore suspects that, contrary to long-held assumptions, the microproteins play a key role in a variety of cellular functions. The young proteins might also be heavily involved in evolutionary development thanks to comparatively rapid “innovations and adaptations.” “It’s possible that evolution is more dynamic than previously thought,” says van Heesch.

Proteins only found in humans

The researchers were surprised to find that the vastly younger microproteins could interact with the much older generation. This observation came from experiments performed using a biotechnical screening method developed at the Max Delbrück Center in 2017. In collaboration with Dr. Philipp Mertins and the Proteomics Platform, which the Max Delbrück Center operates jointly with the Berlin Institute of Health at Charité (BIH), the miniproteins were synthesized on a membrane and then incubated with a solution containing most of the proteins known to exist in a human cell. Sophisticated experimental and computer-aided analyses then allowed the researchers to identify individual binding pairs. “If a microprotein binds to another protein, it doesn’t necessarily mean that it will influence the workings of the other protein or the processes that the protein is involved in,” says Schulz. However, the ability to bind does suggest the proteins might influence each other’s functioning. Initial cellular experiments conducted at the Max 

Delbrück Center in collaboration with Professors Michael Gotthardt and Thomas Willnow confirm this assumption. This leads Ruiz-Orera to suspect that the microproteins “could influence cellular processes that are millions of years older than they are, because some old proteins were present in the very earliest life forms.” 

Unlike the known, old proteins that are encoded in our genome, most microproteins emerged more or less “out of nowhere – in other words, out of DNA regions that weren’t previously tasked with producing proteins,” says Ruiz-Orera. Microproteins therefore didn’t take the “conventional” and much easier route of being copied and derived from existing versions. And because these small proteins only emerged during human evolution, they are missing from the cells of most other animals, such as mice, fish and birds. These animals, however, have been found to possess their own collection of young, small proteins.

The smallest proteins so far

During their work, the researchers also discovered the smallest human proteins identified to date: “We found over 200 super-small proteins, all of which are smaller than 16 amino acids,” says Dr. Clara Sandmann, the study’s third lead author. Amino acids are the sole building blocks of proteins. Sandmann says this raises the question of how small a protein can be – or rather, how big it must be to be able to function. Usually, proteins consist of several hundred amino acids. 

The small proteins that were already known to scientists are known as peptides and function as hormones or signal molecules. They are formed when they split off from larger precursor proteins. “Our work now shows that peptides of a similar size can develop in a different way,” says Sandmann. 

These smallest-of-the-small proteins can also bind very specifically to larger proteins – but it remains unclear whether they can become hormones or similar: “We don’t yet know what most of these microproteins do in our body,” says Sandmann.

Yet the study does provide an inkling of what the molecules are capable of: “These initial findings open up numerous new research opportunities,” says van Heesch. Clearly, the microproteins are much too important for researchers to keep ignoring them. Van Heesch says the biomolecular and medical research communities are very enthusiastic about these new findings. One conceivable scenario would be “that these microproteins are involved in cardiovascular disease and cancer, and could therefore be used as new targets for diagnostics and therapies,” says Hübner. Several U.S. biotech companies are already doing research in this direction. And the team behind the current paper also has big plans: Their study investigated 281 microproteins, but the aim now is to expand the experiments to include many more of the 7,000 recently cataloged microproteins – in the hope that this will reveal many as-yet-undiscovered functions. 

Text: Janosch Deeg 

Photo: An evolutionarily young protein that arose de novo in Old World monkeys: The microprotein in the mitochondria (green) and in the nucleus (blue) was overexpressed in human cells. The yellow and pink areas show that the signal of the microprotein overlaps with the mitochondrial and nuclear signals.

© Clara-Louisa Sandmann, Max Delbrück Center

Source: Press Release Max Delbrück Center
Evolution: Miniproteins appeared “from nowhere”

Research, Innovation, Patient care, Education / 17.02.2023
Jury selects the best in youth science contest

Schoolgirls in conversation with the jury of the competition (Photo: Peter Himsel)
Schoolgirls in conversation with the jury of the competition (Photo: Peter Himsel)

“Mach Ideen groß” is the theme of this year’s nationwide “Jugend forscht” competition. At Campus Berlin-Buch the young scientists presented more than 20 projects. Seven of them made it to the regional championship.

For two days, the campus invited participants to the “Jugend forscht” regional competition in Buch. Children and young people from the 4th grade up to the age of 21 took part. They presented their projects to the jury, the press, and the public – the contest was finally allowed to take place once again after a hiatus due to the pandemic. The winners will go on to compete in Berlin’s statewide competition.

An the winners are...

Three first-place winners and teams emerged from the fields of work, physics and mathematics/computer science: "How stress influences learning" by Dunja Jovicic and "The magnetic, mechanical oscillator" by Konstantin Groth and Rufus Patge were honored. With their artificial intelligence that can detect plant diseases, Elora Marx and Alois Bachmann took first place in the mathematics/computer science category and also received the Max Delbrück Center's special prize: free tickets to the Long Night of Science.

The younger students up to the age of 14 qualified for the state competition with four projects in the "Schüler experimentieren" category: In biology, Yannick Corleisen won with a concept on how to generate electricity and heat from organic waste. Lukas Link found “The best rainbow milk recipe” and took first place in the chemistry section. Xavier Taron Aurelius Volm and Dominik Marcel Rein were also first place winners. They investigated particulate matter pollution during gardening activities (Work Environment); Kai Lehmann was also a regional winner, competing with his project "Generating electricity at home" (Physics).

In addition to the 1st to 3rd places and special prizes sponsored by the research institutions on campus, the Campus Berlin-Buch GmbH "Resource Efficiency" prize went to Raghda Khalaf. The student submitted her project "New Sources of Electricity: Bridging Today and Tomorrow" without personnel or financial support in a shelter for refugees.

The campus sponsors

Campus Berlin-Buch is one of four host venues for “Jugend forscht” in Berlin. The competition’s sponsors include the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch GmbH and – as an associate sponsor – the Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center and Charité – Universitätsmedizin Berlin. They are in charge of organizing a program for the regional round – from the introductory event to the presentations and their evaluation by the jury to the award ceremony.

“The participants come up with surprising ideas and approaches every time,” says Dr. Ulrich Scheller, managing director of Campus Berlin-Buch GmbH. “The competition offers young people a unique chance to actually implement their ideas and see if they work – while inspiring others as well. The kids can also experience science close up on our campus. I’d definitely recommend giving this competition a try.”

About the competition

“Jugend forscht” is Germany’s biggest and best-known competition for the next generation of researchers. It is a joint initiative of the federal government, the magazine Stern, the business and scientific communities, and schools. The aim is to support talented achievers in the areas of science, technology, engineering and mathematics (STEM). Young researchers compete against each year in seven subject areas. Gifted children up to the age of 14 can take part in the junior segment “Schüler experimentieren,” while “Jugend forscht” is open to young people from the age of 15 onwards. The non-profit association Stiftung Jugend forscht e.V. organizes the competition.

Text: CBB & MDC

Further information

Research / 09.02.2023
Salt cuts off the energy supply to immune regulators

Salt disrupts the function of immune regulators (Tregs): Their mitochondria temporarily produce less energy, thus altering cellular metabolism. © Felix Petermann, Max Delbrück Center
Salt disrupts the function of immune regulators (Tregs): Their mitochondria temporarily produce less energy, thus altering cellular metabolism. © Felix Petermann, Max Delbrück Center

Regulatory T cells ensure that immune responses happen in a controlled way. But eating too much salt weakens these cells’ energy supply, thus rendering them dysfunctional for a while. This may have implications for autoimmunity, an international team – including Dominik Müller – reports in “Cell Metabolism.”

Eating too much salt, which is common in many Western societies, is not only bad for our blood pressure and cardiovascular system – it could also adversely impact the immune system. An international research team, coordinated by scientists at the VIB Center for Inflammation Research and Hasselt University in Belgium as well as the Max Delbrück Center in Germany, is now reporting in “Cell Metabolism” that salt can disrupt key immune regulators called regulatory T cells by impairing their energy metabolism. The findings may provide new avenues for exploring the development of autoimmune and cardiovascular diseases.

A few years ago, research by teams led by Professor Dominik Müller at the Max Delbrück Center for Molecular Medicine and the Experimental and Clinical Research Center, a joint institution of Charité – Universitätsmedizin Berlin and Max Delbrück Center (ECRC) in Berlin, Germany and Professor Markus Kleinewietfeld at the VIB Center for Inflammation Research and Hasselt University in Belgium, as well as by colleagues of theirs, revealed that too much salt in our diet can negatively affect the metabolism and energy balance in certain types of innate immune cells called monocytes and macrophages and stop them from working properly. They further showed that salt triggers malfunctions in the mitochondria, the power plants of our cells. Inspired by these findings, the research groups wondered whether excessive salt intake might also create a similar problem in adaptive immune cells like regulatory T cells.

Important immune regulators

Regulatory T cells, also known as Tregs, are an essential part of the adaptive immune system. They are responsible for maintaining the balance between normal function and unwanted excessive inflammation. Tregs are sometimes referred to as the “immune police” because they keep bad guys like autoreactive immune cells at bay and ensure that immune responses happen in a controlled way without harming the host organism.

Scientists believe that the deregulation of Tregs is linked to the development of autoimmune diseases like multiple sclerosis. Recent research has identified problems in mitochondrial function of Tregs from patients with autoimmunity, yet the contributing factors remain elusive.

“Considering our previous findings of salt affecting mitochondrial function of monocytes and macrophages as well as the new observations on mitochondria in Tregs from autoimmune patients, we were wondering if sodium might elicit similar issues in Tregs of healthy volunteers,” says Müller, who co-heads the Hypertension-Mediated End-Organ Damage Lab at the Max Delbrück Center and the ECRC.

Previous research has also shown that excess salt could impact Treg function by inducing an autoimmune-like phenotype. In other words, too much salt makes the Treg cells look like those involved in autoimmune conditions. However, exactly how sodium impairs Treg function had not yet been uncovered.

Salt interferes with mitochondrial function of Tregs

The new international study led by Kleinewietfeld and Müller and first-authored by Dr. Beatriz Côrte-Real and Dr. Ibrahim Hamad – both of whom work at the VIB Center for Inflammation Research and Hasselt University in Belgium – has now discovered that sodium disrupts Treg function by altering cellular metabolism through interference with mitochondrial energy generation. This mitochondrial problem seems to be the initial step in how salt modifies Treg function, leading to changes in gene expression that showed similarities to those of dysfunctional Tregs in autoimmune conditions.

Even a short-term disruption of mitochondrial function had long-lasting consequences for the fitness and immune-regulating capacity of Tregs in various experimental models. The new findings suggest that sodium may be a factor that could contribute to Treg dysfunction, potentially playing a role in different diseases, although this needs to be confirmed in further studies.

“The better understanding of factors and underlying molecular mechanisms contributing to Treg dysfunction in autoimmunity is an important question in the field. Since Tregs also play a role in diseases such as cancer or cardiovascular disease, the further exploration of such sodium-elicited effects may offer novel strategies for altering Treg function in different types of diseases,” says Kleinewietfeld, who heads the VIB Laboratory for Translational Immunomodulation. “However, future studies are needed to understand the molecular mechanisms in more detail and to clarify their potential relationship to disease.”

Text: VIB

Source: Press Release Max Delbrück Center
Salt cuts off the energy supply to immune regulators

Research / 03.02.2023
How the body’s defenses keep their weapons in check

© AG Blankenstein, Technologieplattform „Advanced Light Microscopy“, Max Delbrück Center
© AG Blankenstein, Technologieplattform „Advanced Light Microscopy“, Max Delbrück Center

The signaling molecules of the immune system should trigger a response only where necessary. To prevent a life-threatening spread to the rest of the body, connective tissue can absorb these molecules like a sponge. A team led by Thomas Blankenstein presents this mechanism in “Nature Immunology.

When the T cells of the immune system communicate, they do so with the help of cytokines. An important member of the cytokine family is interferon-gamma – a protein that activates the body’s defenses, particularly in the fight against viruses and intracellular bacteria. Over the course of evolution, the human body has developed a variety of strategies to prevent the immune response from overshooting its mark. Another important mechanism has now been discovered by a German-French research team led by Professor Thomas Blankenstein, head of the Molecular Immunology and Gene Therapy Lab at Berlin’s Max Delbrück Center.

It all hangs on just four amino acids

In a paper published in the journal Nature Immunology, the scientists explain how interferon-gamma uses four amino acids to bind to the extracellular matrix of connective tissue, which forms a web between individual cells and thus mediates intercellular contact. The study’s first author, Dr. Josephine Kemna, explains that this binding prevents the cytokine from spreading throughout the entire body and triggering dangerous immune responses. When the amino acids required for binding are lacking, she says, the result is a serious impairment of the body’s defenses. Kemna was a member of Blankenstein’s team from 2017 to 2022. Last year, she moved to the Berlin biotech company T-knife Therapeutics – a spin-off from Blankenstein’s lab. Kemna completed her doctorate with this latest study, in which Charité – Universitätsmedizin Berlin also played a key role. The research was supported by a grant from the Wilhelm Sander Foundation.

The starting point for the study was an observation made by Blankenstein and his team a few years ago: “We noticed that the molecular structure of the cytokine interferon-gamma differs greatly from species to species,” explains Dr. Thomas Kammertöns, another member of the team who also works at the Institute for Immunology at Charité. He supervised Kemna’s doctoral thesis together with Blankenstein and is listed as last author. “However, one short sequence of four amino acids, known as the KRKR motif, has remained practically unchanged over the entire evolution of vertebrates – i.e., over 450 million years – in all 50 species we studied.” Based on this finding, the team deduced that the KRKR motif must play an important role in the function of the cytokine – and decided to test this hypothesis.

Quickly turning toxic in the blood

The researchers started out using a mouse model developed by Kammertöns, which allowed them to regulate the concentration of interferon-gamma that was produced. “We were already able to determine from this model that interferon-gamma becomes toxic very quickly, and that animals with high concentrations of this signaling molecule in their blood fall ill within a few days,” explains Kammertöns. Biochemical analyses also revealed that once the protein is secreted via the T cells with its four positively charged amino acids, it binds to the negatively charged extracellular matrix – namely, to the molecule heparan sulphate.

“This ensures that interferon-gamma is retained locally, and prevents it spreading throughout the body,” says Kammertöns. However, given that the structure of heparan sulphate differs depending on the tissue, cell type or even cell state, the ability of connective tissue to bind interferon-gamma can also vary, adds Professor Hugues Lortat-Jacob of the Université Grenoble-Alpes, who was also involved in the study.

In the next step, the group turned to Dr. Ralf Kühn, head of the Genome Editing & Disease Models Lab at the Max Delbrück Center, to help develop a model that would produce interferon molecules without a KRKR motif. To do this, Kühn and his team removed the four amino acids from the cytokine in mice using the CRISPR-Cas9 gene editing technique. “For a long time, scientists have believed that the signaling molecule is dependent on this binding site to function at all,” Kammertöns says. “So we first had to prove that this is not the case.” And the team was indeed able to show that, even without the KRKR motif, interferon-gamma still attaches to its receptor on the surface of cells and performs its usual role in the immune response.

Highly potent defense mechanisms

Usually, the immune system would then fight the viral infection and eventually eliminate it. However, for the mice lacking the four amino acids in their interferon-gamma, that was not the case. “The animals’ immune systems were still able to regulate immune responses for viruses that elicit only very brief inflammatory reactions,” Kammertöns reports, saying that in these cases, the amount of interferon-gamma in the blood did initially increase but then fell again very quickly. “Yet when the mice were infected with LCM viruses, which cause a flu-like disease called lymphocytic choriomeningitis and keep the immune system busy for a longer period of time, the gene-edited mice quickly became ill due to the high concentrations of interferon-gamma in their blood.”

“In my view, it is clear from our research that our immune system has developed highly potent mechanisms to keep its own defenses in check,” says first author Kemna. If these mechanisms fail to work properly, she says, the immune system can end up damaging its own organism due to the toxic effect of certain molecules as they continue to spread. “The mechanism we have uncovered shows that evolution has ensured toxic molecules generally act only where they are needed – that is, where the T cell recognizes a virus-infected cell.”

Protection against deadly infection

“This study is of fundamental importance for immunology and our understanding of many inflammatory diseases in the human body,” says Kammertöns. He also explains that the extracellular matrix has a different structure in males and females, so the newly discovered mechanism could explain why some infectious and autoimmune diseases progress so differently in men and women. “We would never have made these new findings without the outstanding collaboration with our French colleague Hugues Lortat-Jacob, who has been researching extracellular matrices for more than 30 years and is one of the world’s leading experts in this field,” Kammertöns adds.

Kammertöns is now planning the next phase of the study with his group leader Blankenstein and scientists at University Medical Center Freiburg. Together, they are going to test their latest findings on a new model. “We want to work with so-called wildlings – mice that have already undergone several infections and whose immune systems therefore elicit a response more similar to that of a human,” Kammertöns says.

“Over the course of its evolution, the immune system has developed increasingly powerful weapons in a sort of arms race against pathogens,” summarizes Blankenstein. “Our work has uncovered a new mechanism that acts a counter balance to this arsenal of weapons without reducing the efficiency of the immune response – just four amino acids in interferon-gamma prevent infectious diseases from causing many more deaths.” It therefore makes sense going forward to gain a better understanding of the exact details of the interaction between interferon-gamma and the extracellular matrix.

Text: Anke Brodmerkel

Picture:

Microscopic analysis of a 16µm-thick cross-section through a tissue in which the immune signaling molecule interferon gamma (IFNγ) has been released: The nuclei of the tissue can be seen in blue, the interferon in green, blood vessels in yellow, and heparan sulfate in red. Areas where the interferon binds the heparan sulfate appear orange. The scale bar marks 10µm in the cross-section.

© AG Blankenstein, Technologieplattform „Advanced Light Microscopy“, Max Delbrück Center

Source: Joint press release of Max Delbrück Center and Charité – Universitätsmedizin Medizin
How the body’s defenses keep their weapons in check

Research, Innovation / 01.02.2023
Lausanne University Hospital Investigates Use of PENTIXAFOR in Cardio-Vascular Setting

The Lausanne University Hospital (CHUV) has reported the initial dosing of a patient in a phase II clinical study investigating the sensitivity of PENTIXAFOR (Boclatixafotide) in a cardiovascular and inflammatory setting. It is the first time that Eckert & Ziegler’s proprietary CXCR4-compound is used in an advanced clinical test in a non-cancer indication, opening the way for a broader use of PENTIXAFOR outside of oncology.

The Gallium-68 based radio-diagnostic PENTIXAFOR promises to significantly improve the sensitivity in the detection of acute myocardial inflammation, which may allow for future early clinical management of patients with myocarditis, avoiding the progression to more severe stages.

To investigate the potential of PENTIXAFOR the CHUV will recruit, on its own account, up to 60 patients in a so-called investigator initiated study (ISS). Eckert & Ziegler, owner of the rights to the CXCR4 targeted tracer used in this study, supports the CHUV team under Professor John Prior and Professor Niklaus Schaefer by providing the compound. Also, part of the CHUV team is Professor Margret Schottelius, Head of the Translational Radiopharmaceutical Sciences lab at CHUV/Agora, who was involved in the preclinical development and clinical translation of PENTIXAFOR and Dr Judith Delage, Head of the Radiopharmacy Unit, in charge, together with her team, of the clinical transfer and of the GMP internal production.

Acute myocardial inflammation is a heterogenic inflammatory disease of the heart muscle involving different clinical pathologies and outcome. The CHUV study focuses on the three entities acute cellular cardiac allograft rejection, cardiac sarcoidosis and the immune checkpoint inhibitor induced myocarditis, as non-invasive diagnosis remains challenging for these life-threatening conditions with current standards.

“Including cardiovascular indications in our prognostic development program in addition to oncology demonstrates the exciting potential of PENTIXAFOR,” comments Dr Jens Kaufmann, co-founder and general manager of Pentixapharm. “We are delighted to collaborate with an excellent centre such as the CHUV in this field, led by Dr Christel Kamani as principal investigator.”

Dr Kamani is triple-certified in cardiology (2017), internal medicine (2018) and in nuclear medicine (2022). Dr Kamani has learned all techniques of multimodality cardiovascular imaging. His research interest focuses on non-invasive multimodality tools for the detection of cardiovascular disease.

PENTIXAFOR is being developed by Eckert & Ziegler’s subsidiary Pentixapharm GmbH primarily as a superiorly sensitive diagnostic for rare blood cancers, among them myelomas, lymphoma and leukaemia.

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.
Contributing to saving lives.

About Lausanne University Hospital
The Lausanne University Hospital (CHUV) is one of Switzerland's five university hospitals and a well-known center of medical education and research thanks to its collaboration with the Faculty of Biology and Medicine of the University of Lausanne and the Swiss Federal Institute of Technology in Lausanne (EPFL).

Source: Press Release EZAG
Lausanne University Hospital Investigates Use of PENTIXAFOR in Cardio-Vascular Setting

Research / 24.01.2023
ERC Proof of Concept Grant for Mina Gouti

Dr. Mina Gouti © Pablo Castagnola, MDC
Dr. Mina Gouti © Pablo Castagnola, MDC

Organoids have to be fed and cared for continuously so that they can mature. So far, it is mostly a manual process – not suitable for industrial drug screening. Now, the European Research Council (ERC) has awarded Mina Gouti a Proof of Concept Grant to tackle scalability and reproducibility.

Dr. Mina Gouti and her colleagues are developing highly complex organoids from the reprogrammed stem cells of patients with neuromuscular diseases like spinal muscular atrophy (SMA). “The children experience paralysis in the first months of life, and in the end they can’t even breathe,” says Gouti, who heads the Stem Cell Modeling of Development and Disease Lab at the Max Delbrück Center. “Our neuromuscular organoids, we call them NMOs, can help us understand exactly why the motor neurons of SMA patients die and find ways to stop this process. And that’s just one example of many different diseases that can be studied using NMOs.”

But to develop new therapies – and get robust results – her lab needs to make thousands of similar NMOs at the same time. The researchers are facing the same challenges as the entire field: reproducibility and scalability. “For advanced 3D cell culture systems such as ours to reach their full potential, we need to develop automated, reliable, and high-throughput approaches that are also capable of meeting industry requirements,” Gouti says. The European Research Council (ERC) agrees with this assessment and is now funding her efforts to achieve automation with a Proof of Concept (PoC) Grant of €150,000. Gouti is one of 366 researchers from all over Europe who are receiving PoC funding in the 2022 competition, paving the way for them to translate their findings from ERC Consolidator Grant projects into broadly applied solutions.

Standardized care for organoids

Organoids are a bit like babies: They have to be fed and cared for continuously to keep them happy so that they can mature. “At the moment, most of my lab is busy generating these complex organoids manually,” Gouti says. “It’s labor-intensive and expensive. Plus, the results can vary from one ‘caregiver’ to another.” She wants to automate each step of the process and create a more controlled environment.

In order to teach a robot how to nurture organoids, she is teaming up with the Pluripotent Stem Cell Platform of Dr. Sebastian Diecke, which already has an appropriate system in place. Additionally, her lab’s high-throughput imaging system will take pictures of the organoids at various time points, with artificial intelligence assessing their morphology and size. “That is the beauty of working at the Max Delbrück Center,” she says. “It enables this sort of collaboration – one that boosts each other’s research. And if we are successful, we will have robust data and much more time to analyze disease mechanisms.”

High-throughput drug screening, however, poses yet another challenge. Once the organoids are 50 to 100 days old – just mature enough to model neuromuscular diseases – they measure five to six millimeters and are too big to fit into standard 96-well microtiter plates. “We need to miniaturize them,” Gouti says. “So one question is how to keep them small but functional. The other question is: Can we speed up maturation if they don’t need to grow that much?”

Step by step, Gouti and her colleagues are improving the technology, making it available to other labs in Berlin and – hopefully – Big Pharma. “I’m super happy to start this process,” Gouti says. “Our ultimate goal is to establish NMOs as a new preclinical model for drug testing. I’m convinced that they can help to reduce animal studies. And even more importantly, many patients with rare neuromuscular diseases are desperately waiting for therapies.”

Further information

 

Source: Press Release Max Delbrück Center
ERC Proof of Concept Grant for Mina Gouti

Research, Innovation / 03.01.2023
Deep expertise, and a bold vision: MyoPax launches in Berlin

Prof. Dr. med. Simone Spuler (left) and Dr. med. Verena Schöwel-Wolf (Photo: Felix Petermann, Max Delbrück Center)
Prof. Dr. med. Simone Spuler (left) and Dr. med. Verena Schöwel-Wolf (Photo: Felix Petermann, Max Delbrück Center)

MyoPax develops regenerative therapies for previously incurable muscle diseases. An interview with co-founders Prof. Simone Spuler and Dr. Verena Schöwel-Wolf, now board member and CEO respectively

MyoPax emerged from the Max Delbrück Center and Charité. What’s your company all about? 

Dr Schöwel-Wolf: Muscle disorders can drastically reduce quality of life and are potentially life-threatening. In Prof. Simone Spuler’s lab at the Experimental and Clinical Research Center (ECRC), our team has developed an innovative stem cell technology that could fundamentally change this situation. With the new method, it is now possible to produce pure and highly regenerative muscle stem cells that have the potential to rebuild human muscles and replenish their stem cell pools for the long term. Through the use of cell engineering and gene editing technologies, we are developing, for the first time ever, therapies for local muscle defects, acute muscle wasting disorders, and hereditary muscular dystrophies that were previously untreatable or insufficiently treatable.

Prof. Spuler: Our start-up is breaking new ground, and that requires courage. Our model doesn’t exist yet. But our team has been combining muscle research with clinical work at the Outpatient Clinic for Muscle Disorders for many years already. It is clinically and scientifically experienced and has the necessary regulatory and manufacturing expertise.

How were you supported during the spin-off phase?

Dr. Schöwel-Wolf: The Max Delbrück Center help moved our project forward in its incubator, especially through the PreGoBio and SPOT programs. The Berlin Institute of Health (BIH) significantly boosted and accelerated therapy development via its SPARK program. We also received support from a number of other sources, ranging from the ECRC’s technology platform to the Helmholtz Validation Fund, the Else Kröner-Fresenius Foundation, and the Gisela Krebs Foundation, to the German Federal Ministry of Education and Research, which is funding our first-in-human clinical trial. Ascenion and the technology transfer unit of Charité provided assistance during the patenting process.

MyoPax has been accepted into the incubator program of the Copenhagen-based BioInnovation Institute (BII) Foundation.

Dr. Schöwel-Wolf: We are thrilled to have found another inspiring network in Europe. Through our second company, MyoPax Denmark ApS, we have received a €1.3 million convertible loan from the BII Foundation. This is the starting point for building MyoPax into a globally competitive business. BII is also providing strategic guidance on business development issues.

What are you tackling first?

Dr. Schöwel-Wolf: In 2023, we will be launching a trial focusing on a rare children’s disease in which the bladder’s sphincter muscle doesn’t fully develop. This muscle defect is due to a disruption in cell migration during embryonic development and causes lifelong incontinence. We aim to restore this muscle by generating muscle stem cells from a muscle biopsy and injecting the cells right there where they are missing. The fact that this disease is characterized by a well-defined muscular defect makes it well suited for testing the safety and efficacy of our therapeutic approach for the first time.

Prof. Spuler:  On top of that, when it comes to rare diseases, it’s possible to apply for provisional marketing authorization after the first clinical trial. Rare diseases are well protected by regulatory bodies, especially from competition. We are scheduled to complete this first trial in 2026.

What are the next milestones?

Prof. Spuler: We are developing three therapeutic platforms. The first technology uses the patients’ natural muscle stem cells to repair muscular defects that are not caused by a genetic disorder. The second platform under development focuses on hereditary muscular dystrophies. Here, we seek to treat individual muscles with the patient’s own cells. Gene editing tools are used to correct the genetic defect in the cells outside the body. The cured cells are then injected into the muscle. In this way, we produce a personalized therapy for each patient. The third platform is the furthest away from a clinical trial. Here, induced pluripotent stem cells are used to generate the muscle stem cells. This process is based on blood cells, which are available in large non-patient-specific batches, thus making the technology faster and more cost-effective.

Interview: Christine Minkewitz / Campus Berlin-Buch GmbH

Source: The interview first appeared in the 02/2022 issue of the magazine buchinside.

Further information

Innovation / 20.12.2022
Change in the Supervisory Board of Eckert & Ziegler AG

Eckert Wagniskapital und Frühphasenfinanzierung GmbH has appointed radiation physicist Paola Eckert-Palvarini as its new representative on the Supervisory Board of Eckert & Ziegler AG (ISIN DE0005659700, SDAX). She replaces sinologist Jutta Ludwig, who will move to the Executive Board of Eckert & Ziegler AG as Asia Representative as of January 01, 2023.

Ms. Eckert-Palvarini studied physics in Milan and in the past was, among others, member of the board at Eckert & Ziegler BEBIG SA, which was listed on the Brussels EURONEXT. The native Italian owns shares in Eckert & Ziegler AG's major shareholder Eckert Wagniskapital und Frühphasenfinanzierung GmbH and has been familiar with the group of companies for a long time.

Innovation / 19.12.2022
Changes in the Management Board of Eckert & Ziegler

The founder and CEO of Eckert & Ziegler AG (ISIN DE0005659700, SDAX), Dr. Andreas Eckert, today gave notice to the company that he intends to transfer from the Management to the Supervisory Board after the company’s General Shareholder Meeting in mid-2023. Before that the Supervisory Board appointed, for a period of two years effective 1 January 2023, two additional new Executive Directors, Dr. Hakim Bouterfa as Chief Medical Officer and Jutta Ludwig as Head of Asia. Both are already with the Eckert & Ziegler and shall now, albeit on the Board level, support Dr. Harald Hasselmann, whom Eckert recommended as his successor.

Triggering the restructuring was the recent endorsement of the European Medicine Agency of Eckert & Ziegler’s phase III registration study. It necessitated an adjustment of senior management assignments and opened an opportunity to pass on responsibility to a new group of executives. Eckert, who heads the group now for more than 30 years, is one of the longest serving CEOs among German listed companies and wants to withdraw from operational activities.

Eckert Wagniskapital und Frühphasenfinanzierung GmbH, who holds more than 30% of the shares of Eckert & Ziegler and the right to nominate members of the Supervisory Board, supports the transfer of Eckert, so that the change will be in line with the regulations of the German Stock Corporation Act and the recommendations of the German Corporate Governance Code.

www.ezag.com

Research / 14.12.2022
Understanding the transition to disease

Photo: David Ausserhofer/MDC
Photo: David Ausserhofer/MDC

As part of the IMMEDIATE project, a team led by ECRC researcher Friedemann Paul is investigating inflammatory precursors of diseases – and how nutrition and the gut microbiome influence the immune system. The project is receiving more than €7 million in EU funding.

Chronic inflammation is the root cause of many organic diseases. Yet what happens at a molecular level in the body during this transition from health to illness is still largely unknown. With its project IMMEDIATE, a European team now wants to shed more light on these poorly understood processes and find out to what extent nutrition and the gut microbiome could be altered to prevent diseases from developing in the first place.

A total of 12 European institutions are participating in IMMEDIATE, which stands for “imminent disease prediction and prevention at the environment host interface.” The project coordinator is Professor Friedemann Paul, director of the Experimental and Clinical Research Center (ECRC) of the Max Delbrück Center and Charité – Universitätsmedizin Berlin, and professor at the NeuroCure Clinical Research Center at Charité. 

The project will be funded for the next four years by the European Union’s Horizon Europe program to the tune of almost €7.2 million in total. A good €1.6 million of this will go to Charité; the Max Delbrück Center will receive around €1 million. The European Research and Project Office (EURICE) is also significantly involved in the planning and implementation of the large-scale project.

Searching for biomarkers

“First, we want to better understand the inflammatory processes that precede organ dysfunction or damage,” Paul explains. “We also want to identify biomarkers that can be detected before disease symptoms even occur.” For their investigations, the researchers will employ methods including state-of-the-art omics technologies and make use of clinical data and biosamples from three ongoing observational studies. “These studies are the German National Cohort (NAKO), a cohort of patients who have received kidney transplants called KTx360°, and an Israeli cohort,” adds Dr. Chotima Böttcher from the ECRC, who is helping to coordinate IMMEDIATE. 

Professor Tobias Pischon’s Molecular Epidemiology Lab at the Max Delbrück Center is playing a key role in the search for biomarkers. “We will use a proteomic approach to measure a variety of inflammation markers,” says Pischon. “Since we are mainly interested in disease precursors, we want to identify molecular signatures associated with changes in cardiovascular and renal function as well as metabolism.” His team will then investigate the similarities and differences between these signatures in different diseases.

An inflammation-reducing microbe

Further steps are planned parallel to these investigations: “The main goal of the project is to understand how and why interventions such as dietary changes and the administration of special microbiota change the composition of the gut microbiome – and how the metabolic products of the microbes influence the immune system,” explains Dr. Sofia Forslund, head of the Host-Microbiome Factors in Cardiovascular Disease Lab at the Max Delbrück Center and ECRC. 

The hope, Forslund says, is that this knowledge can then be used to prevent disease and promote health. Her team will be primarily responsible for developing the necessary infrastructure and analytical methods to pull together the huge amounts of data generated by omics technologies and evaluate these data with the help of artificial intelligence. The other participating teams on Campus Berlin-Buch are Dr. Philipp Mertins’ Proteomics Lab, Dr. Jennifer Kirwan’s Metabolomics Lab, Dr. Nicola Wilck’s Immune-Microbial Dynamics in Cardiorenal Disease Lab, and Dr. Anja Mähler’s Clinical Research Unit. 

The IMMEDIATE consortium is also planning its own intervention studies, including a study with around 200 hospital workers. “These test subjects are often under a great deal of stress due to their job and usually eat rather unhealthily and at irregular times,” explains Böttcher. “So we assume that they will have elevated inflammation levels.” One thing the researchers want to find out is whether the administration of the anti-inflammatory microbe Akkermansia muciniphila can change the biomarkers of the test subjects and improve their general well-being.

Support from apps 

Mobile apps developed by the IMMEDIATE team in cooperation with patient advocacy organizations will help them gather information in this study. “For example, the test subjects can enter how stressful their day was, as well as when and what they ate,” explains Böttcher. The apps also provide feedback and tips to help the users integrate proven health-promoting measures into their own lives – enabling changes to be made before they even reach the disease threshold.  

Text: Anke Brodmerkel 

Source: Joint Press Release of the Charité and the Max Delbrück Center
Understanding the transition to disease

economic development / 13.12.2022
Glycotope with South Korean partner against breast cancer

Therabest and Glycotope to assess Therabest’s iPSC-derived NK cell product TB-100 in combination with Glycotope’s GT-00AxIL15 immuno-cytokine for development in triple negative breast cancer

San Diego, U.S.A., Seoul, Korea and Berlin, Germany, 13 December 2022 – Therabest USA. Inc, Therabest Korea (Therabest) and Glycotope GmbH (Glycotope) have signed an agreement to assess the clinical development of Therabest’s EiNKTM (Enhanced iPSC-derived NK) cell therapy, TB-100, in combination with Glycotope’s immuno-cytokine, GT-00AxIL15 in triple-negative breast cancer (TNBC) patients.

NK cell therapies from various cell sources have demonstrated exciting results in early clinical trials and are rapidly becoming powerful alternatives to conventional treatments. However, for solid tumors, NK cell therapies are still hampered by the low persistency and homing of NK cells. The combination of Therabest’s iPSC derived NK cell therapy TB-100 and Glycotope’s tumor-targeted immuno-cytokine GT-00AxIL15 challenges the current NK cell therapy paradigm by converging a two-component platform in which the dosage of an immuno-cytokine improves the activity of TB-100.

“We look forward to maximizing the strengths of TB-100 and GT-00AxIL15 to challenge solid tumors with enhanced cytotoxicity, specificity, persistency, and safety through this collaboration. We expect serial killing of MUC1 positive TNBC tumor cells by TB-100 redirected with GT-00AxIL15,” said Sung Chang Lee, CEO, Therabest USA and adjunct CDO, Therabest. 

“The collaboration underlines the attractivity of our tumor targeted immuno-cytokine GT-00AxIL15 and its suitability for combination therapies. We are excited by the potential of combining two highly innovative technologies to explore the treatment of TNBC here,” added Henner Kollenberg, CEO, Glycotope. 

Therabest’s EiNKTM platform is a next-generation allogeneic NK cell therapy manufacturing technology that covers all processes from iPSC gene editing to iPSC-derived NK cell differentiation and proliferation. TB-100, a highly active NK cell therapy development candidate from EiNKTM platform, can recognize and remove heterogeneous cancer cells very effectively. TB-100 is an off-the-shelf and uniform cell therapy without donor-dependent batch-to-batch variation with minimal risk of current cell therapies.

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.

www.glycotope.com/

economic development / 07.12.2022
OMEICOS Therapeutics Announces Expansion of OMT-28 Clinical Development Program into Primary Mitochondrial Diseases

OMT-28’s established safety profile, biomarker data, and funding secured from existing investors enable swift transition into a Phase II clinical study

OMEICOS, a biopharmaceutical company developing first-in-class small molecule therapeutics based on the reimagining of omega-3 fatty acid metabolism and physiology, announced the closing of a new financing round and the expansion of its clinical development activities into an indication with high unmet medical need - Primary Mitochondrial Disease (PMD). The financing, led by Remiges Ventures, Vesalius Biocapital and SMS group GmbH, will allow OMEICOS to advance its lead program, OMT-28, into a first Phase II study in PMD patients in H1 2023. OMT-28 had shown an excellent safety profile in two clinical trials and 162 individuals in total and profound effects on key biomarkers of metabolic and inflammatory stress such as GDF-15, IL-6, PTX-3 and hs-CRP.

“The expansion of OMT-28’s clinical development program into PMD will allow us to gain further evidence on the compound’s capability to target mitochondrial dysfunction and associated inflammation as well as to obtain first clinical response data from this group of severely affected patients that still have very limited treatment options”, commented Dr. Robert Fischer, CEO/CSO of OMEICOS Therapeutics. “With the initiation of the upcoming Phase II study in PMD, OMEICOS is immediately positioned as a clinical-stage developer in an attractive rare disease market with a significant unmet medical need. In this indication, OMEICOS benefits from the unique blend of expertise in cardiology and muscle cell physiology combined with the profound understanding of the multimodal effects of our molecules in metabolic and inflammatory stress pathways.”

Defects of the mitochondrial oxidative phosphorylation system (OXPHOS) results in oxidative and reductive stress and chronic activation of pro-inflammatory pathways, leading to disease progression and ultimately reduced life expectancy in many indications, including PMD. While PMD’s are a highly heterogeneous group of diseases, high energy requiring tissue and organs are most affected and as a consequence, myopathies and cardiomyopathies represent two of the key hallmarks in several PMD patient populations.

About OMEICOS
OMEICOS Therapeutics has discovered a series of metabolically robust synthetic analogues of omega-3 fatty acid-derived epoxyeicosanoids that have the potential to treat mitochondrial dysfunction, inflammatory, cardiovascular and other diseases. Epoxyeicosanoids activate cell type-specific endogenous pathways that promote organ and tissue protection. OMEICOS’ small molecules are orally available and show improved biological activity and pharmacokinetic properties compared to their natural counterparts. For more, please visit: www.omeicos.com

Research / 22.11.2022
ERC Starting Grants for Berlin scientists

They have their sights set on serious diseases: Gabriele G. Schiattarella analyzes mechanisms of heart failure, Simon Haas wants to improve immunotherapies for leukemia and Michael Sigal would like to prevent gastrointestinal diseases. Now, the ERC is awarding the researchers with a Starting Grant.

A Starting Grant from the European Research Council (ERC) is considered a major seal of approval for junior researchers. In addition to prestige, it provides about €1.5 million in funding over five years while also opening doors to other opportunities and attracting high-quality applicants for PhD and postdoc positions. The ERC looks for novel approaches that could open up new frontiers and spur significant advances (“high risk, high reward” research). The researchers must have completed their doctorate within the last two to seven years and have a scientific track record showing great promise. Dr. Gabriele G. Schiattarella, Dr. Simon Haas and Professor Michael Sigal, all of them guest scientists at the Max Delbrück Center, have now been awarded this highly sought-after grant:  

Schiattarella is head of the guest research group “Translational Approaches in Heart Failure and Cardiometabolic Disease” at the Max Delbrück Center in Buch, which is funded by the German Center for Cardiovascular Research (DZHK). He also works at the Department of Internal Medicine and Cardiology at the Charité – Universitätsmedizin Berlin. The ERC Starting Grant will allow him to launch his project KetoCardio, where he will investigate how ketone bodies – by-products of fat metabolism – impact on heart failure with preserved ejection fraction (HFpEF). He is receiving €1.8 million for his work. 

Simon Haas leads the junior research group “Systems Hematology, Stem Cells & Precision Medicine” of the Berlin Institute of Health at Charité (BIH), which is part of the joint focus area “Single-Cell Approaches to Personalized Medicine” of the BIH, the Max Delbrück Center, and Charité. His team is based at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB), where it operates as a guest group. He plans to use the ERC Starting Grant to study interactions between immune cells and leukemia cells in order to find out why immunotherapy is effective in some leukemia patients but not in others. His project is called “InteractOmics”. 

Michael Sigal is a clinician scientist at the Charité Department of Hepatology and Gastroenterology. At MDC-BIMSB he heads the Emmy Noether Independent Junior Research Group „Gastrointestinal Barrier, Regeneration and Carcinogenesis" funded by the German Research Foundation. With his project "Revert" the guest scientist hopes to explain how the gastrointestinal epithelium changes in the wake of an injury. This knowledge could serve as a basis for developing therapies that target the underlying causes of inflammatory intestinal diseases and contribute to the prevention of colorectal cancer.

The projects in detail

Rebooting cardiac metabolism

HFpEF is a very common form of heart failure – more than 30 million people worldwide are affected by this syndrome. “In the years ahead, it will become the leading cause of heart failure,” says Schiattarella. In HFpEF, it is not the heart’s pumping power that is excessively impaired, but its capacity of relax (elasticity). As a result, the cardiac muscle cannot take in enough blood to supply the body with sufficient oxygen and nutrients. People with HFpEF experience a reduced exercise tolerance, fluid accumulation in the lungs and the rest of the body, and shortness of breath. Currently, little is known about the molecular mechanisms of the disease and barely any drugs exist to treat it. 

Schiattarella’s group discovered that HFpEF patients have elevated levels of ketones in their blood, which are by-products of the body breaking down fat. When our cells do not receive sufficient glucose – during fasting or exercise, for example – the body burns fat instead. This produces ketones, or ketone bodies, which function as an alternative source of energy for cells. “They are powerful fuel for cell metabolism,” says Schiattarella. “Cells also use them to communicate changes in their metabolism.” 

Schiattarella wants to investigate what it is that stimulates ketone metabolism in HFpEF and why. “It may be the body’s way of providing the affected heart muscle cells with more energy, or compensating for damage,” the researcher supposes. He also wants to clarify whether and how ketones, particularly the most common ketone ß-hydroxybutyrate (ß-OHB), regulate chromatin structure, gene transcription, and signaling in cardiac muscle cells – thus affecting their elasticity, for example. Finally, he wants to develop therapeutic strategies to further increase ketone levels in HFpEF – whether through diet adaptations, specific exercise training, or drugs. 

The scientist and his team have a wide range of technologies at their disposal at the Max Delbrück Center. “We will develop various animal models and combine proteomics, transcriptomics, and genomics approaches,” says the researcher. “That and the project’s three main areas of focus – ketones metabolism, their signal transmission, and the development of ketone-based therapeutic strategies – make KetoCardio a big deal in cardiovascular research.” 

How leukemia and immune cells interact 

Leukemia occurs when immature immune cells stop developing but keep dividing and eventually inundate the blood. There, they encounter mature and active immune cells that either recognize and kill the cancer cells or let them escape. So far, little is known about the interactions between immune cells and leukemia cells. “But gaining that knowledge would show us why the immune system sometimes overcomes the leukemia cells and sometimes fails,” says Haas. “And why immunotherapy is effective in some patients but not in others.” 

Haas is planning to modify single-cell analysis so that the method can capture the interactions and communication between all immune cells and cancer cells. Haas and his team are located at MDC-BIMSB, which offers outstanding technical infrastructure for their work. “Instead of looking at individual cells, we’re aiming to investigate millions of cell pairs as they interact with each other,” he says. “These doublets will tell us who is binding to whom, and what happens in the process.”   

The scientists are starting by investigating mice that have leukemia. By looking at their blood, the team can see how the disease develops at different stages, how it advances, and how it can be stopped. His clinical collaboration partners are providing Haas with samples from leukemia patients.  “Once we understand what disease stage the cells are in when they meet, and the developmental stage of the immune cells and the cancer cells, we’ll have a better understanding of how the immune response works and how the leukemia fights back,” he says.  

Immunotherapies, which fight cancer using the body’s own immune system, are already being used in the treatment of leukemia. But they only work in a fraction of the patients who receive them. “If we can take cell pairs from the blood of patients for whom the therapy worked and compare them with pairs from patients who weren’t so lucky, we’ll hopefully be able to identify which circumstances need to be present for the immune system to beat the leukemia.” His goal is to be able to predict which patients are likely to benefit from immunotherapy (which is a very complex and costly form of treatment), and how the therapy can be refined so that it works in more patients.

Understanding the threshold to colorectal cancer 

The stomach and intestines are exposed to a wide variety of external factors. They are therefore lined by a protective cell layer that is continually regenerated: the epithelium. Michael Sigal focuses primarily on stem cells, which are responsible for the continuous regeneration of this barrier between the body and the outside world. An Emmy Noether Independent Junior Research Group under his direction is investigating how these stem cells can potentially be damaged, and also how this damage contributes to the development of infectious and inflammatory diseases as well as cancer.  

So far, the team has demonstrated that an injury of the intestinal mucous membrane can lead to a reorganization of cellular hierarchy. When stem cells located deep inside the mucous membrane die, they are replaced by fully differentiated cells from the surface. The latter are reprogrammed into stem cells and begin to divide, thus regenerating the mucous membrane. This regeneration process prevents bacteria in the gut from entering the bloodstream after an injury. However, Sigal hypothesizes that it may also represent the first step in the development of colorectal cancer.  

“Cells from the surface of the epithelium come into contact with the microbiome – the bacteria that colonize our intestines – and their metabolites, some of which can cause DNA damage,” he says. “If they become stem cells, mutations can become fixed in the epithelium, disrupting the complex processes that normally ensure an equilibrium between cell division and differentiation – the first step towards the development of cancer.”  

During the next five years, he hopes to explain what changes take place in the gastrointestinal epithelium in the wake of an injury. For his project “Revert”, he uses technologies such as single-cell sequencing and lineage-tracing to compare the daughter cells of normal stem cells with those of “replacement stem cells” and to document genetic changes over time. Sigal hopes to develop a fundamental understanding of which factors contribute to the manifestation of chronic diseases of the intestine. This knowledge could serve as a basis for developing therapies that target the underlying causes of inflammatory intestinal diseases and contribute to the prevention of colorectal cancer. 

Text: Charité, BIH, Jana Ehrhardt-Joswig

Source: Press Release Max Delbrück Center
ERC Starting Grants for Berlin scientists

Research / 17.11.2022
Cancer researcher Ulrike Stein receives high honor

Prof. Dr. Ulrike Stein (Photo: David Ausserhofer/Max Delbrück Center)
Prof. Dr. Ulrike Stein (Photo: David Ausserhofer/Max Delbrück Center)

Ulrike Stein is searching for molecules that play a key role in metastasis, aiming to use them as therapeutic targets for solid tumors and to improve cancer prognosis. The Metastasis Research Society has recognized her work with this year’s Women in Science Achievement Award.

Cancer patients rarely die from the primary tumor, but rather from the metastases that form when tumor cells spread to other sites in the body. How the cells achieve this is not fully understood. Uncovering the molecular mechanisms of metastasis in order to identify new targets for cancer therapies is the goal that drives Professor Ulrike Stein. She leads the Translational Oncology of Solid Tumors Lab at the Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center and Charité – Universitätsmedizin Berlin. The renowned Metastasis Research Society has recognized Stein with this year’s Women in Science Achievement Award for her exceptional contributions to this field. The award ceremony is held in Buenos Aires on November 16. She is the second cancer researcher to receive this award since its inception in 2020.

Just over ten years ago, Stein made her most important discovery: Together with Professor Peter M. Schlag of Charité’s Comprehensive Cancer Center (CCCC) and Professor Walter Birchmeier of the Max Delbrück Center, she identified the metastasis-associated in colon cancer 1 (MACC1) gene, which was completely unknown at the time. When cancer cells express MACC1, their ability to proliferate, move around the body, and invade other tissues is enhanced. MACC1’s role as a key factor and biomarker of tumor growth and metastasis – not only in colorectal cancer, but in more than 20 solid tumors such as gastric, liver and breast cancer – has since been studied by many other researchers worldwide and confirmed in more than 300 publications.

A child of the GDR

Stein grew up in the town of Naumburg in Saxony-Anhalt. She knew as early as seventh grade that she wanted to be a cancer researcher. But despite her determination, it was a rocky road to get there. After finishing her Abitur, she applied for one of five study places in the GDR for genetics. As she had a perfect 1.0 grade point average, she didn’t think there would be a problem but was rejected.

She was instead offered a spot to study biochemistry at Martin Luther University in Halle. She grudgingly accepted – and was surprised to discover when she began her studies that they centered on the biochemistry of plants. She stuck with it anyway, and in the last leg of her studies she managed to veer toward cancer research, completing her thesis at the Central Institute for Cancer Research of the GDR Academy of Sciences, one of the three institutes from which the Max Delbrück Center later emerged.

She also enrolled at the Academy of Sciences for her doctorate. But shortly after the fall of the Wall in November 1989, when she was ready to submit the required 16 copies of her dissertation, she learned the Academy had lost the right to award doctorates. It wasn’t until a year later, after German reunification, that she was able to receive her doctorate from Humboldt University in Berlin. “After reunification, I was the very first scientist to defend her doctoral dissertation at Humboldt University,” Stein recalls. She then spent three years as a postdoc at the Max Delbrück Center before moving with her husband in 1994 to the National Cancer INstitute (NCI) in Maryland, USA, where she investigated how cancer cells become resistant to chemotherapy drugs.

Doing research in the US was like heaven

If she and her husband hadn’t noticed that their son was beginning to have problems with the German language, “I never would have returned to Germany,” she says. She was especially taken by the technical and financial resources of the institute and by the collaboration among colleagues. “I thought I was in heaven,” she enthuses even today. After her return she became a research group leader, first at the Max Delbrück Center and then at Charité’s former Robert Rössle Clinic. In 2003 she qualified as a professor at Charité, and since 2007 has led her own lab at the ECRC. But she kept up her ties with the United States. For about 15 years, she and her husband spent their summer vacations at the NCI in Frederick, Maryland, where she continued doing research with her old colleagues through an alumni program of the Alexander von Humboldt Foundation. As Stein’s lab at the ECRC grew, though, she eventually had no time for that anymore.

What excites her about cancer research is the intellectual challenge, Stein says, “to be able to make a difference and help people with my own ideas.” She is always looking for genuinely novel topics. “If other scientists are already working on something, there’s no need for my lab to pursue that too,” she explains. This search for uncharted territory led her to metastasis research, an area she feels is somewhat neglected.

“I always wanted to do cancer research”

Stein and her team are currently looking for inhibitors of MACC1. Together with Dr. Robert Preißner of Charité, she has discovered that statins, which are prescribed as cholesterol-lowering drugs, can inhibit MACC1 expression in tumor cells. After experimental studies in cell lines and mouse models and a retrospective data analysis of human samples, a clinical trial is now planned. She says a great deal of patience and perseverance is required to translate basic research findings into clinical practice.

She has never run out of either. Neither then, when studying plant biochemistry, nor now, when writing research proposals or journal papers. When she needs some time off from work, she goes with her husband to their thatched cottage on the Baltic Sea, taking a good book or some scientific literature with her. She comes back with countless new ideas. “I always wanted to do cancer research,” she says with conviction. “I would never give that up.”

The Women in Science Achievement Award is the latest of many honors bestowed on Stein. These include the 2010 Prize of the Berlin-Brandenburg Academy of Sciences and Humanities, donated by the Monika Kutzner Foundation for the Advancement of Cancer Research, for the discovery of MACC1; and the 2014 Felix Burda Award in the category “Best Prevention Idea” for research on colorectal cancer, which she received together with Professor Ulrich Rohr of Hoffmann-La Roche and Professor Peter M. Schlag. For the latter award, Stein and her collaborators had developed a blood test for early cancer detection, based on the MACC1 gene. With the blood test, it is possible, at a very early stage of colorectal cancer to identify patients who are at high risk of developing life-threatening metastases. Stein is pleased that her work is being recognized in this way. “But what I really want,” she says, “is to bring these MACC1 inhibitors and diagnostics into clinical use. I am convinced that these would lengthen patients’ lives.”

Text: Jana Ehrhardt-Joswig

Further information

Stein Lab

Translational Oncology of Solid Tumors

Research / 15.11.2022
Highly cited – and influential

Sofia Forslund, Friedemann Paul and Nikolaus Rajewsky are among the Highly Cited Researchers 2022. Each year, the company Clarivate lists researchers who have demonstrated significant influence in their field. In addition, Research.com has ranked Klaus Rajewsky as one of the world’s best scientists.

The “Highly Cited Researchers” list identifies researchers who are having a significant impact on the research community based on the rate at which their peers cite their work. The preliminary list is drawn from papers that rank in the top 1% by citations for field and publication year in the Web of Science citation index over the past decade. Combining quantitative and qualitative approaches, bibliometric experts and data scientists at the US company Clarivate Analytics then compile a “who’s who” of influential researchers. Starting in 2022, Clarivate has partnered with Retraction Watch and extended the qualitative analysis, addressing increasing concerns over potential misconduct.

This year’s list features 6,938 individual researchers from nearly 70 countries. The majority of them work in the United States of America (2,764), followed by scientists from China (1,169), the United Kingdom (579) and Germany (369) – such as Dr. Sofia Forslund, Professor Friedemann Paul and Professor Nikolaus Rajewsky. 

Furthermore, Research.com publishes the “Best Scientists in the World 2022 Ranking”. The company lists Professor Klaus Rajewsky among the top 500 worldwide, and as number 15 in Germany. The first edition of this ranking is based on data collected from Microsoft Academic Graph in December 2021.

About our scientists

Dr. Sofia Forslund is a junior group leader at the Experimental and Clinical Research Center (ECRC), a joint institution of Charité – Universitätsmedizin Berlin and the Max Delbrück Center. The Swedish bioinformatician creates data-based models that show how we and our gut microbiome develop together toward health or disease. 

Professor Friedemann Paul is Director of the Experimental and Clinical Research Center (ECRC), a joint institution of Charité – Universitätsmedizin Berlin and the Max Delbrück Center. His Clinical Neuroimmunology Lab focuses on improving therapeutics and diagnostics for diseases such as multiple sclerosis. During the pandemic, the team has also started to work on post COVID-19 syndrome. 

Professor Nikolaus Rajewsky wants to detect diseases as they develop in the cells and fight them before they begin to cause damage. The systems biologist is Scientific Director of the Berlin Institute of Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB), where he heads the Systems Biology of Gene Regulatory Elements Lab. He is establishing networks at all levels to help cell-based medicine achieve a breakthrough in Berlin and across Europe. 

Professor Klaus Rajewsky established standard methods for researching gene functions and diseases like cancer and he continues to contribute to our understanding of antibody-producing B cells. At the Max Delbrück Center, his team studies the genesis of B cell lymphomas in comparison to normal B cell physiology.  

Further Informationen

Research / 09.11.2022
A second chance for the Sumatran rhino

Sumatra-Nashorn Kertam at the Insel Borneo. Photo: Ben Jastram, Leibniz-IZW
Sumatra-Nashorn Kertam at the Insel Borneo. Photo: Ben Jastram, Leibniz-IZW

Malaysia’s last male Sumatran rhino, Kertam, died in 2019. Now, a team from the Max Delbrück Center has successfully grown stem cells and mini-brains from his skin cells. As they report in "iScience", their goal is to create sperm cells that may help to save the endangered species from extinction.

The Sumatran rhinoceros was once found across large parts of East and Southeast Asia. Today, poaching and habitat destruction have decimated the population of the world’s smallest and most ancient rhino species, leaving only a few dozen individuals living in the rainforests of Sumatra and the Indonesian part of Borneo. As a result, mating encounters between males and females are increasingly rare.

The last of their kind in Malaysia

The Sumatran rhinoceros, which is the only surviving rhino species with hair, has been considered extinct in Malaysia since 2019 following the death of male Kertam and, just a few months later, female Iman. But a team of Berlin scientists led by Dr Vera Zywitza and Dr Sebastian Diecke, head of the Pluripotent Stem Cells Platform at the Max Delbrück Center in Berlin, are not content with this. They and their international partners have an ambitious goal: to turn skin cells taken from deceased Sumatran rhinos into stem cells, from which they can then derive egg and sperm cells to be used in assisted reproduction – in this case, fertilization in the laboratory. The embryos bred in the petri dish, which will be the offspring of Kertam and other already deceased females, will be carried to term by surrogate rhino mothers.

In the scientific journal iScience, the team led by first author Zywitza and last author Diecke has now reported an initial success: they have generated induced pluripotent stem cells, or iPS cells for short, from Kertam’s skin samples. These cells have two key advantages. First, they are able to divide infinitely and therefore never die; and second, they are able to transform into any cell type in the body. For their recently published study, the group has already grown brain organoids, also called “mini-brains,” from Kertam’s iPS cells.

Learning from the white rhino

The technology platform developed its stem cell technologies as part of the BioRescue research project for the even more critically endangered northern white rhinoceros – of which only two females now remain, living in a Kenyan wildlife reserve. “Our current study has benefited a lot from the knowledge gained through this large-scale project, which is funded by the German Federal Ministry of Education and Research,” says Zywitza. Professor Thomas Hildebrandt, head of the Reproduction Management Department at the Leibniz Institute for Zoo and Wildlife Research (IZW) in Berlin, and his research group were also significantly involved in the project.

Zywitza recounts how all those involved in the current study were surprised and pleased to discover that the methods used to turn the skin cells of northern white rhinos into stem cells also worked well with the cells of Sumatran rhinos. Under the microscope, the stem cells of both rhino species were barely distinguishable from human iPS cells. Nevertheless, there were species-specific differences: “In contrast to northern white rhino iPS cells, Kertam’s iPSCs could not be cultivated without feeder cells, which release growth factors that help to keep stem cells in a pluripotent state,” explains Zywitza.

A deeper look into evolution

In addition to preserving the species, the stem cells obtained from Kertam’s skin serve another purpose: “iPS cells from exotic animals provide a unique tool to gain insights into the evolution of organ development,” says Zywitza. To demonstrate this, Dr. Silke Frahm-Barske, who is also a scientist in Diecke’s research group, grew brain organoids from the cells.

“To the best of our knowledge, mini-brains like these have only been obtained from mouse, human, and non-human primates so far,” says Frahm-Barske. “So we were very pleased to see that the stem cells we generated from the Sumatran rhino formed organoids quite similar to those of humans.” However, she added that the team had to treat the human and rhino iPS cells slightly differently in order to cultivate the brain organoids.

The next step is sperm cells

The team’s next goal is to use Kertam’s iPS cells to grow sperm suitable for artificial insemination. “This step is more difficult,” says Zywitza. “To obtain sperm cells, we first need to use the iPS cells to cultivate primordial germ cells – the precursors of eggs and sperm.” This is the tricky task the scientists are now going to tackle. They also plan to obtain iPS cells from other Sumatran rhinos.

Reproduction expert Thomas Hildebrandt explains why efforts like these are necessary: “Measures are indeed being taken in Indonesia to preserve the Sumatran rhino population by bringing together the remaining individuals in wildlife reserves,” he says. “But females that have not been pregnant for a long time often become infertile, for example due to cysts that develop on their reproductive organs, or they may just be too old to bear young.”

“Even though our work is attempting to make the seemingly impossible possible – to ensure the survival of animals that would otherwise probably disappear from our planet – it must remain an exception and not become the rule,” emphasizes Zywitza. “Despite all the buzz around what we are doing in the lab, this can at best make a small contribution to saving these rhinos from extinction. The protection and conservation of the animals’ few remaining habitats is equally important at least.”

Text: Anke Brodmerkel

Source: Press Release Max Delbrück Center
A second chance for the Sumatran rhino

Innovation / 08.11.2022
Eckert & Ziegler: Nine-Month Figures Show Strong Sales Growth

Eckert & Ziegler Strahlen- und Medizintechnik AG (ISIN DE0005659700, SDAX) increased sales by 25% to EUR 164.0 million in the first nine months of 2022. Net income of EUR 23.3 million was EUR 5.8 million lower than in the same period of the previous year, in which the sale and associated deconsolidation of the tumor irradiation device division generated one-off income of approximately EUR 9.4 million. Adjusted for this one-time effect, consolidated net income attributable to EZAG shareholders increased by around 18% year-on-year from EUR 19.7 million to EUR 23.3 million. This increase in earnings was due to favorable exchange rates as well as higher sales of industrial products and radiopharmaceuticals.

The Isotope Products segment generated sales of EUR 102.7 million, up EUR 29.6 million (+40%) compared to the first nine months of 2021. All main product groups contributed to this good performance. The development of oil and gas prices is boosting the exploration activities of energy companies and, consequently, the demand for measurement components. Around EUR 7.9 million of the increase was attributable to the acquisition of the Argentine company Tecnonuclear SA; a further EUR 7.0 million was due to a favorable US dollar exchange rate (+12% on average between the first three quarters of 2021 and 2022)

Sales of EUR 65.5 million in the Medical segment during the first nine months of the year were around 6% higher than last year (EUR 61.6 million). The main growth driver continues to be the pharmaceutical radioisotopes business. Sales of laboratory equipment and plant engineering also increased significantly.

Despite the positive nine-month figures, the Executive Board continues to adhere to its previous sales and earnings forecast for the fiscal year 2022 of around EUR 200 million and around EUR 27 million, respectively. This position is based on the currently tense and risky global economic situation.

The complete quarterly report can be viewed here:
https://www.ezag.com/fileadmin/user_upload/ezag/investors-financial-reports/englisch/euz322e.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.
Contributing to saving lives

Research, Innovation / 01.11.2022
ASC Oncology proudly announces new partnership with Tamer Group

Dr. Christian Regenbrecht, CEO of ASC Oncology and Yasser Khattab, Sales Director of Tamer Group, sign the Memorandum of Understanding for a strategic partnership. (Photo: ASC Oncology)
Dr. Christian Regenbrecht, CEO of ASC Oncology and Yasser Khattab, Sales Director of Tamer Group, sign the Memorandum of Understanding for a strategic partnership. (Photo: ASC Oncology)

Cancer does not stop at borders - and neither does an approach to personalized cancer therapy developed in Berlin. Reverse Clinical Engineering® is now available to oncologists and cancer patients in Saudi Arabia, the Middle East, and North Africa.

Across borders, cancer is one of those diseases that is unpredictable, malignant and, despite high research efforts, not yet conquered. About 19.3 million people worldwide are diagnosed with cancer every year, and at the same time the prescribed chemotherapy fails in about half of all cancer patients. It is therefore essential to make advances in personalized cancer treatment available to doctors and cancer patients around the globe as quickly as possible and in a responsible manner.

Therefore, the Berlin-based biotech company ASC Oncology GmbH ("ASC Oncology") thinks beyond borders and is committed to the international use of Reverse Clinical Engineering® test procedure. The possibility that patients and oncologists know, based on scientific data, which drug is likely to work for an individual patient before a drug therapy is started should become a matter of course worldwide.

As an important next step in this journey, ASC Oncology today proudly announces its strategic partnership with Tamer Group. Through their century-long history, associated healthcare experience and the Tamer Group's large network in the Kingdom of Saudi Arabia, the Middle East and North Africa, the Reverse Clinical Engineering® testing procedure will thus become accessible to many patients as an important approach to personalized cancer therapy.

Tumor researcher Dr. Christian Regenbrecht, co-developer of the Reverse Clinical Engineering® procedure, emphasizes the benefits of the new partnership for cancer patients and treating physicians: "For three years, we have been using the testing procedure to support oncologists and patients in optimally individualising cancer treatment. With Reverse Clinical Engineering®, we test different drug treatment options before starting therapy and thus find the therapy option that is most likely to have an effect on the individual patient's tumor. Outside the patient's body and thus without side effects. This is a key step on the road to establishing personalized cancer therapy, which we are now taking together with the Tamer Group."

Reverse Clinical Engineering® enables oncologists to offer their patients effective therapy from the outset. Using a tissue sample of the patient's tumor taken during a biopsy or tumor surgery, 3D copies of the tumor, called organoids, are grown in the laboratory. In the next step, various cancer drugs are tested on these organoids to determine their effectiveness on the individual patient's tumor. In this way, on the one hand, a probably unsuccessful therapy can be prevented from unnecessarily burdening the cancer patient and, on the other hand, the chance of a therapeutic response can be significantly improved.

 

Who is ASC Oncology?

ASC Oncology was founded by nine leading scientists from the fields of expertise pathology, tumor biology, biochemistry, biotechnology and molecular biology in 2019 with the aim of addressing the most important challenge of modern oncology: Providing patients with the right therapy at the right time. In doing so, ASC Oncology scientists are stepping up to advance precision medicine internationally through the Reverse Clinical Engineering® procedure developed in Berlin to partner with oncologists to provide cancer patients with the best possible therapy from the start. Our goal is to provide better care to more patients than ever before in the history of oncology. ASC Oncology - Rethink Oncology.

www.asc-oncology.com