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Semb Lab Behind the Scenes
Andreas Weiss | Helmholtz Munich

Handcrafted Langerhans Islets: New Hope for Type 1 Diabetes Patients?

Our organs do a remarkable job day in and day out, without ourselves even having to think about it. Our body has its own ventilation system, a clearance system for toxins, and a system to balance energy homeostasis. But what if one of these systems stops working? People with type 1 diabetes must replace the job of an essential part of the pancreas – coming with many costs. Helmholtz Munich researchers like Henrik Semb want to help these patients: he is engineering artificial Langerhans islets, the part of the pancreas where insulin is produced.

Our organs do a remarkable job day in and day out, without ourselves even having to think about it. Our body has its own ventilation system, a clearance system for toxins, and a system to balance energy homeostasis. But what if one of these systems stops working? People with type 1 diabetes must replace the job of an essential part of the pancreas – coming with many costs. Helmholtz Munich researchers like Henrik Semb want to help these patients: he is engineering artificial Langerhans islets, the part of the pancreas where insulin is produced.

Having type 1 diabetes is a hard job: the underlying cause of the autoimmune disease is a lack of insulin-producing pancreatic beta cells. Hence, the patients need to replace the function of these cells themselves and become dependent on the external delivery of insulin. To survive, they continuously monitor their blood sugar levels and inject the correct amounts of the hormone insulin. This is necessary to transport the sugar from their food into their body cells. In severe cases only transplantation of beta cells from human donors allows the patients to regulate their blood sugar levels. However, donor organs are scarce. What if there was a way to produce new insulin-producing beta cells in the lab and transplant them into the patient?

Handcrafted beta cells from the laboratory

For the last decades, Helmholtz Munich researcher Henrik Semb has been following the question of whether cell transplantation of lab-generated beta cells could be a more sustainable solution for people living with diabetes. He and his team use pluripotent stem cells in cell culture and transform them into beta cells that can be transplanted into patients. The challenge: to produce fully functional beta cells from human pluripotent stem cells, while avoiding the presence of other cell types. “We can already generate insulin-producing beta cells from stem cells in the lab. Our next step is to pioneer a manufacturing pipeline to produce these beta cells at clinical grade, ready to use in phase 1 clinical trials,” says Henrik Semb, who is leader of ISLET and director of the Helmholtz Munich Institute of Translational Stem Cell Research. ISLET is an EU consortium with top international researchers from seven institutions united in one vision: bringing stem cell-based therapy in type 1 diabetes to reality. Together, the researchers aims to prepare for the first clinical trials in Europe where stem cell-derived beta cell transplants are tested in people with type 1 diabetes. But Henrik Semb and his collaborators are already thinking one step ahead: They want to engineer functional Langerhans islets.

Better together: Transplanting Langerhans Islets instead of beta cells only

Ultimately, the researchers want to transplant a product consisting of glucagon-producing alpha cells and insulin-producing beta cells ­ just like the real Langerhans islets. Glucagon and insulin are the two main hormones in our body that regulate energy homeostasis. While glucagon increases blood sugar levels, insulin lowers blood sugar levels. “Previous work has shown that cell-cell interactions within the islet, particularly between the two major cell types, the beta cell and the alpha cells, are important for the fine-tuning of regulating insulin release,” explains Henrik Semb. In animal models, the transplantation of both cell types together achieved much better blood sugar regulation. This would also have enormous advantages for humans as it could reduce the risk of secondary diseases later in life. Eunike Setyono, a doctoral researcher at Helmholtz Munich, is hopeful that ISLET’s new product can one day help patients and improve their quality of life. She works in the team of Heiko Lickert, director of the Helmholtz Munich Institute of Diabetes and Regeneration Research and a member of ISLET.

Still a long way ahead

Stem cell-based cell replacement therapy for type 1 diabetes is as close to a cure as possible, but the researchers still need to overcome many obstacles before the transplantation of lab-generated islets can give realistic hopes to type 1 diabetes patients. The biggest problem comes with the root of the disease: autoimmunity. Even if type 1 diabetes patients receive new beta cells, their immune system is still programmed to destroy them. “A big question in the field at the moment is whether we can make the cells we transplant hypoimmune. Can we genetically engineer the cells so the immune system will not recognize them?” asks Henrik Semb together with his team and collaborators. Right now, transplantation of beta cells requires the intake of immunosuppressive drugs to prevent the immune system from destroying the transplant. Shutting down the body’s immune system obviously comes with many side effects for the patients – like increased susceptibility to infections or an increased risk for cancer. This is only worth the cost for patients with extreme trouble controlling their blood sugar levels by insulin injections. “To get to our final product is a little bit like a walk in the Death Valley. It's extremely complicated and also very expensive. But through funding from the EU and the support by Helmholtz Munich we've established a really good program in Europe for this kind of research,” explains Henrik Semb.

Vision for the future

“The ultimate goal is to provide alternative sources of beta cells as replacement therapy. This would be the first causal therapy of type 1 diabetes,” says Heiko Lickert. One day, transplantation of stem cell-derived insulin-producing beta cells might provide type 1 diabetes patients with a natural cellular controller of blood sugar levels. This would enable more precise control of blood sugar levels compared to the available devices to monitor blood sugar levels and inject insulin. Henrik Semb is optimistic that they can test their product in clinical trials by 2026.