When the experts meet in Hamburg in July for the most important global congress in stem cell research – the ISSCR Annual Meeting – many regional players from the Life Science Nord cluster will also be there. A guide to the region’s major players in research and industry in the stem cell field.

What are stem cells used for in biomedicine?

Stem cells are the driving force behind development and regeneration in the human and animal body. In comparison to highly specialized body cells, stem cells are less committed to a specific direction of development. As multi-talented cells, they combine the special property of being able to multiply as stem cells in their undifferentiated form with the ability to develop into specialized cell types.
They are therefore suitable as a biological basis for research and treatment approaches in medicine. Healing with cells – this is the central concept of regenerative medicine. It aims to replace or renew damaged cells, tissue or organs in order to make them functional again.

Depending on their origin, stem cells are versatile in different ways.

• Somatic or adult stem cells are the regeneration reserve for tissues and organs. They provide the necessary cell replenishment when cells in the tissue die and need to be replaced. The transplantation of blood stem cells is a well-established treatment method for patients suffering from leukemia or other blood diseases. However, tissue stem cells are difficult to multiply in the laboratory.
• The situation is different with so-called pluripotent stem cells, which are derived from embryos that are just a few days old: They can be cultivated in the laboratory in very large quantities and transformed into almost all specialized cell types of the human body. This makes these cellular all-rounders a potentially infinite source of material for biomedicine. The discovery of reprogramming revolutionized the field: body cells can be artificially reverted to an embryonic all-rounder state in the laboratory. The result of this transformation are induced pluripotent stem cells (iPS cells).

Pluripotent stem cells open up many new fields of application: They can be used to develop model systems for disease research in the Petri dish, for drug discovery or drug testing. And last but not least, tissue or cell material for cell replacement therapy. Specialized cell types derived from human pluripotent stem cells are being tested in initial clinical trials worldwide and also in northern Germany.

Where are the hubs of stem cell research in northern Germany?

Ole Pless is an excellent insider in the local stem cell research scene and well connected in the region. The biologist heads the Translational Drug Research at the Hamburg site of the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP ScreeningPort. Among other approaches, stem cell-based test systems are developed at the ScreeningPort, which can be used to examine large collections of chemical molecules for their effectiveness and toxicity in a highly automated manner. “Stem cells help us to create better and more realistic disease models for pharmaceutical research and preclinical development,” says Ole Pless.

This is particularly true for the search for drugs for diseases for which there are currently no treatment options. One of these is Leigh syndrome, a rare disease in which the mitochondria – the cell power plants – are defective due to a genetic mutation. The disease causes movement disorders and mental disabilities and usually leads to death in the first few years of life. A research team from Düsseldorf and Berlin has succeeded in obtaining induced pluripotent stem cells (iPS cells) from the skin cells of Leigh patients. The nerve cells derived from these cells have been used to create the first human model of Leigh syndrome in a petri dish.

An approved drug helps with a rare disease

It is not only suitable for research, but is also an excellent test system for the search for active substances. This has been impressively demonstrated by participants in the European research consortium CureMILS, in which Pless is involved, in an approach known in the pharmaceutical world as “drug repurposing” or “drug repositioning”: Here, drugs that have already been approved for the market are tested in high-throughput screenings for their suitability in completely different areas of medical application.

For me, CureMILS is the blueprint for rapid stem cell-based translation that can bring benefits to patients.

Ole Pless
Fraunhofer ITMP ScreeningPort

“We have tested more than 5,500 active ingredients in the high-throughput process, for which extensive safety and efficacy data is already available.” One hit was sildenafil, which is approved under the name Viagra® for the treatment of erectile dysfunction. And indeed: in individual treatment trials, the drug proved to be well tolerated in children and adults and patients benefited from the treatment. The consortium is planning a Europe-wide multicenter study to further clinically test the effect of sildenafil.
“For me, this is a blueprint for a stem cell-based project that enables rapid translation of research results from the laboratory to affected patients,” says Ole Pless.

The team led by Professor Thomas Eschenhagen and Professor Arne Hansen from the Institute of Experimental Pharmacology and Toxicology at the University Medical Center Hamburg-Eppendorf (UKE) also attaches great importance to the translation of stem cell-based approaches. Eschenhagen is a pioneer in tissue culture. Thanks to modern stem cell technologies, living heart muscle tissue is created in miniature in the UKE laboratories.

Using iPS technology, the Hamburg team produces large quantities of human heart muscle cells. Together with a tissue adhesive and a mold, they produce strips of heart muscle just a few millimeters long – experts call them engineered heart tissue (EHT), which stretch out between two tiny silicone stakes and contract and relax rhythmically – like the wall of a pumping heart muscle.

The EHTs are ideal test objects for new drugs. “If you add certain active ingredients, you can measure exactly how this affects the contraction of the model muscle using video optics,” says Eschenhagen. In 2015, he founded the spin-off EHT Technologies GmbH with Arne Hansen and colleagues, which offers the heart muscle test systems, including analysis software, as compact test benches for the pharmaceutical industry. In the meantime, the gene therapy company DiNAQOR has taken over the start-up (see chapter Company landscape).

Another stem cell expert at the University Medical Center Hamburg-Eppendorf is Boris Fehse: he is Professor of Cell and Gene Therapy at the Clinic for Stem Cell Transplantation at the UKE. His research includes safe methods of permanent genetic modification of blood cells using integrating vectors as well as genome editing for applications in gene therapy and cancer research.  Also at the UKE, Professor Madeleine Bunders is using organoid technology, which allows human organs such as the intestine, liver, lungs and kidneys to be modelled at the microscopic level, to investigate the interactions between human immune cells and tissue development.

At the University of Hamburg, Baris Tursun is researching fundamental mechanisms of stem cell biology – in particular the molecular processes involved in reprogramming cells in the nematode C. elegans, a model organism. One important aspect is how protective mechanisms counteract the reprogramming of cells and influence ageing. “A better understanding of the complex processes and molecular protective mechanisms of cells could thus promote healthy ageing in humans and animals,” says Tursun. However, the findings are also important for medical translation.

Lübeck stem cell platform

Associate Professor Philip Seibler heads the Stem Cell Platform Lübeck at the Institute of Neurogenetics (Director: Professor Christine Klein) at the University of Lübeck. The Institute of Neurogenetics specializes in stem cell-based approaches for research into Parkinson’s disease, a neurodegenerative disease. As a partner of the European StemBANCC consortium, the Lübeck team had already built up a great deal of expertise and an extensive collection of iPS cells from Parkinson’s patients.
This expertise led to the establishment of the Stem Cell Platform Lübeck in 2021. “With the platform, we support both basic research and clinically oriented research at the university in the use of human iPS cells,” says Philip Seibler. In addition, a resource of iPS cell lines from more than 100 individuals is available, which can be passed on for research purposes as part of collaborations. The Lübeck stem cell platform is funded by the German Research Foundation (DFG), among others.

Which companies use and develop stem cell technologies?

Modern bioprocess technology is needed to cultivate and multiply stem cells in the laboratory. The life science company Eppendorf SE from Hamburg supplies the necessary equipment, consumables, software solutions and services in the upstream area. For example, bioprocess control systems with containers made of glass or high-tech plastic, in which stem cells, among other things, can thrive under optimal and controlled conditions. This is not only important for therapeutic applications. Innovative foods such as cultured meat are also produced using specialized bioprocess technology.

The biotechnology company Evotec SE, based in Hamburg, is using induced pluripotent stem cells (iPSCs) in two fields of application – both for early drug research and in the development of regenerative therapies.

“We have built an industrialized iPS infrastructure at our sites in Hamburg, Göttingen and Modena that represents one of the largest and most complex iPS cell platforms in the industry,” says Sandra Lubitz, Senior Vice President of iPSC Drug Discovery at Evotec.

The company has numerous collaborations with academic partners and pharmaceutical developers, including Bristol Myers Squibb (neurodegenerative diseases), Boehringer Ingelheim (eye diseases) and, since April 2024, Bayer (cardiovascular diseases). One of the identified drug candidates from the iPSC drug discovery platform, BMS-986419, has already made it into clinical trials. After a successful phase I study, Bristol Myers Squibb announced that a phase II study for BMS-986419 is planned for 2024.
Another area of focus is allogeneic, iPS-derived cell therapies. These include a beta cell replacement therapy for the treatment of diabetes, which is to be tested in clinical trials with the Canadian partner Sernova at the end of 2025. In Modena, Evotec also has a state-of-the-art cGMP cell therapy manufacturing center.

Our industrialized iPS infrastructure is one of the largest and most complex in the industry.

Sandra Lubitz,
Evotec SE

In the world of regenerative medicine and biomedical research, it is often necessary to transport cells or tissue from one location to another – for example, from the laboratory directly to the treatment room of a clinic. However, freezing and thawing cells usually involves risks, as the sensitive biological material can be damaged or its physiological properties can change.

This is where the Hamburg-based start-up Cellbox Solutions GmbH comes in, a spin-off of the Fraunhofer IMTE in Lübeck. Cellbox Solutions has developed innovative, transportable incubators that can be used to send living cells of excellent quality internationally. This special “warm chain logistics solution” guarantees optimal physiological conditions during the entire transport, in combination with very precise control systems for temperature, CO2 concentration and other parameters for transportation by car, train or plane. The Cellbox meets all regulatory requirements for the rapidly growing market of therapeutic cell therapy. But not only that – organoids, tissue patches or 3D cell structures can also be safely transported with it.

The laboratory technology company Revvity, which emerged from PerkinElmer Cellular Technologies, supports pharmaceutical and biotech companies in accelerating the development of therapies and developing new test procedures in diagnostic laboratories. The Hamburg site, with more than 100 employees, is, among other things, the center of excellence for the production of high-content imaging systems used in stem cell-based screens.

The UKE spin-off, which was founded in 2015 under the name EHT Technologies, was acquired by the Swiss gene therapy company DiNAQOR in 2021 and has since established itself as an independent contract research organization under the name DiNABIOS in the Start-up Labs in Bahrenfeld. Heart muscle constructs based on iPS cells are used for preclinical drug testing.

The Hamburg-based start-up TRI Thinking Research Instruments has developed an integrated automation solution for microscopy, data management and analysis that is particularly suitable for stem cell-based drug research. The system, called VAIDR, combines AI-based image analysis with automatic image data acquisition and subsequent result evaluation, completely eliminating time-consuming and error-prone work steps for researchers. A new product from TRI is aimed at monitoring cell production in the bioreactor.

Peprotech, based in Hamburg, is a laboratory supplier specializing in cell culture media. Growth factors and cytokines are particularly in demand for stem cell research, as they are important for multiplying stem cells and differentiating them into specialized cells. The company is now part of the laboratory equipment giant ThermoFischer Scientific, which has a large portfolio for stem cell research.
Stem cell treatment is becoming increasingly important in many areas of regenerative medicine. A fundamental step in this technology is the isolation of stem cells from various tissues using proteolytic enzymes such as collagenases and neutral proteases.

The pharmaceutical company Nordmark, based in Uetersen in the Hamburg metropolitan region, is one of the world’s largest suppliers of these enzymes. The Nordmark Biochemicals department actively supports customers from the pharmaceutical industry in establishing their cell isolation processes and accompanies them on the way to approval.

Which stem cell-based therapy approaches are being tested?

Blood stem cells are the only stem cells that have been successfully used in clinics for decades. In recent years, treatment has improved significantly, especially in the case of allogeneic blood stem cell transplants, where the transplanted cells come from foreign donors. Stem cell transplant centers are located in Hamburg, Lübeck, Kiel and Flensburg. The stem cell transplant center at the University Medical Center Hamburg-Eppendorf (UKE) is the largest stem cell transplant center in Germany and one of the largest in Europe, performing around 200 allogeneic blood stem cell transplants a year.

But a new generation of stem cell-based therapies is also being tested in the North:

• Heart patches: Patients with heart muscle weakness were implanted with so-called heart patches in the BIOVAT-HF-DZHK study in Göttingen and at the UKSH Campus Lübeck. These are heart tissues cultivated in the laboratory that are produced from induced pluripotent stem cells. This means that the team in Lübeck is also involved in the clinical trial, which is unique worldwide. The results are already promising.
  
• Sickle cell anemia: Dynamic developments in the pharmaceutical world can also be observed in the use of tissue stem cells. This applies in particular to genome-edited blood stem cells, which are the basis for the gene therapy “Exa-cel” for the treatment of sickle cell anemia and beta thalassemia. The US FDA, the British MHRA and the EMA have conditionally approved the product as the first CRISPR-Cas drug for marketing. A milestone for stem cell-based medicine. This therapy is also used at the UKE (I still have to check).
  
• HIV therapy: Stem cell transplantation is also an essential prerequisite for the gene therapy for the treatment of HIV developed by the Hamburg-based company Provirex. The team uses a precise genome editing tool called Brec1 to cut out viral DNA from infected cells. One approach being pursued is to equip the blood stem cells of an HIV patient with the gene scissor – in order to build up an immune system that is resistant to HIV.

Text: Philipp Graf

Article picture © Fraunhofer ITMP/Martin Kunze