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Research

 

In the lab, fundamental diabetes research


 

By investing in fundamental scientific research, we hope that one day diabetes will be a thing of the past. The research projects we support are carried out by top researchers in renowned laboratories worldwide. Currently, the DON Foundation finances up to five research projects. These are carried out in the following laboratories: Hubrecht Institute, Leiden University Medical Centre, Vrije Universiteit Brussel, Hebrew University of Jerusalem and Expertisecentrum Bètacel Bescherming (Expertise Centre Beta Cell Protection). Unlike other organizations, an important part of our strategy is to commit to long-term agreements to give researchers sufficient time to fundamentally test their hypotheses.

 

Expertisecentrum Bètacel Bescherming (Expertise Centre Beta Cell Protection)

 

 The first Dutch attempt to cure diabetes type 1


 

Prof. dr. Bart Roep, immunologist at the Leiden University Medical Center (LUMC), is trying to understand with his researchers how excatly type 1 diabetes arises. With this knowledge, he not only wants to prevent type 1 diabetes to appear, but also cure the illness. A perspective exactly in line with the goal of the stichting DON.

According to Roep, 2016 was a special research year for multiple reasons. “First, our research showed us how diverse type 1 diabetes (T1D) really is. Small, molecular differences hide under the same clinical picture, which need a custom approach.”

In addition, 2016 was the first time Roep could test on humans if vaccinating against T1D with an advanced cell therapy was feasible and safe. “It was the first ‘made in Holland’ attempt to actually cure T1D,” he says, “and a big step with regards to repressing the immune system with medicine, with all the risks this entails.”

The variation in the disease between patients means that there might not be a ‘magic bullet’ treatment and that it might not be possible for one standard therapy to work for every patient. Roep: “Moreover, we discovered that most people with T1D still have beta cells, even if they barely produce any insulin. This discovery only makes intervening in the disease process more urgent, even long after the diagnosis has been made. After all, there might be beta cells left to save, to activate.”

It’s a lot of hard work, but ultimately we are convinced that diabetes can be eradicated. One way or another.

 

Prof. dr. Bart Roep Ph.D.

Expertise Centre Beta Cell Protection

Finally, the research group of Roep has made a breakthrough in understanding the origin of type 1 diabetes. “It is not the immune system that makes a mistake, but the stressed out beta cells,” he explains. “The immune system does what it needs to, namely cleaning up unhealthy tissue. Because those stressed out beta cells send out signals that the immune system can interpret as an infection or an early tumour formation. That still makes T1D the result of an immune response and so an immunological affliction.”

This insight is important because it helps us understand where these differences in the disease process come from, what lies at the base of it. Roep: “And so also why certain therapeutic strategies can work for some patients with T1D, but not for others. This new knowledge allows us to make the first steps towards personalized medicine; towards precision medicine that allows us to attempt a customized treatment for each individual patient. An approach we have known longer for cancer.”

With the insight that the beta cell plays a large role in its own fate, therapy can now also be developed to make the islets of Langerhans – which house the beta cells – ‘happy’ again. It is a new, supplementary approach to the immune therapy to stop the disease. Roep: “With the support of Stichting DON in recent years, we were able to force a breakthrough in understanding the disease process. We also learned how to cure people with T1D and why. This is the first step towards personalized medicine in T1D.”

Prof. dr. Bart Roep Ph.D.

  • Immunologist, diabetes researcher at the LUMC
  • Received 1.5 million EUR for research into a vaccine against type 1 diabetes, jointly from the DON Foundation and the Diabetes Foundation.
  • Notable quote: “People are sceptical: ‘So much money for research that is taking so long? Surely, it’s not rocket science? No, it’s harder than rocket science! NASA receives 20 billion per year, but Man has still not set a foot on Mars. We do our research with a lot less money, and it is at least as difficult!”

 

Hubrecht Institute

A log for stem cell development


 

For Eelco de Koning, 2016 was basically the year of the detail. Let us zoom in on a patient with type 1 diabetes. The problem is located in the pancreas. More specifically, in the islet of Langerhans. In those islets, we are concerned with the beta cells. Until recently, a beta cell could not really be removed from a pancreas or islet. Last year, De Koning, together with Alexander van Oudenaarden, used a technique which allowed them to characterize individual cells more accurately than ever before. A breakthrough.

De Koning: “Compare an islet of Langerhans with houses made of Lego. The roofs are made of red blocks, the walls white, the doors green… Until know, we could only view the entire house, to the average of all those blocks. For the first time, we could map out each individual block, which means each individual cell. Without ‘contaminating’ the surrounding blocks. This offers completely new perspectives.”

What kinds of perspectives exactly? “For the first time, we now find very rare populations in the islets, for example of cells that have characteristics of a stem cell. With this technique, we can pick them out, which we described in two great scientific articles that were published in prestigious journals.”

In 2014 my research team won the ‘Breakthrough Prize’. This was because we discovered how to detect pancreatic stem cells, remove them in their purest form, and transform them in a laboratory into very large amounts of tissue. This was a global breakthrough.

Our discovery has brought us one step closer to creating a correctly functioning pancreas.

prof. dr. Hans Clevers Ph.D.

Hubrecht Institute

In the LUMC, the tests were done on human islets, while many of the analyses took places in the group of Alexander of Oudenaarden at the Hubrecht Institute. De Koning: “We also applied the technique at embryonic cells of the mouse and identified various populations of stem cells there. Already inside an embryo! Apparently, it is all even more complex than we suspected. What is interesting about the technique is that it not only identifies various cells. It also enables us to track the development of one type of cell. Because a beta cell develops itself step by step out of a stem cell.” What do these phases look like? De Koning: For the first time, we now have the tools to minutely map out each separate phase of the lifeline from stem cell to beta cell. That is how we are composing a log of the development.”

Such a log may sound less exciting, but it is really the recipe with which researchers will finally cultivate beta cells. De Koning: “With the right signals and the optimal cultivation medium, this in principle allows us to steer the stem cell into the direction of a beta cell step by step. Compare it to an assembly line that produces cars at the end of a conveyor belt. 2016 was the year in which we learned a lot about the development of individual cells.”

Hans Clevers - stichting DON

Prof. dr. Hans Clevers Ph.D.

  • Geneticist, diabetes researcher at the Hubrecht Institute, Professor at the University Medical Centre [UMC] Utrecht
  • Received an amount of 750,000 EUR from the DON Foundation for research into beta cells
  • Notable quote: “One way or another, it is very glamorous to commit yourself to the cancer cause. We will all be climbing the Alpe d’Huez, and we’ll be growing a moustache in November. All very well, but diabetes certainly deserves as much attention.”

Vrije Universiteit Brussel

What does a malaria medicine have to do with type 1 diabetes?


 

In his project Beta cell Neogenesis (BENE), Harry Heimberg researches how new beta cells can be created. It is his attempt to answer the large problem of type 1 diabetes (T1D), which is the loss of beta cells.

“Huge progress has been made in this field during the last decade,” says Heimberg. “In that period, it became clear that the desired beta cells can be created from both embryonic stem cells and from adult cells. This last is possible after reprogramming into stem cells. For now, it is unclear whether the beta cells created in these ways will find their way to use in the clinic.”

Linked to his research, the most important development to Heimberg is showing that beta cells can be made out of other cells of the adult pancreas. Heimberg: With support of DON, we successfully researched that perspective in recent years and we managed to transform acinar cells (pancreas cells that normally produce digestion enzymes) into beta cells. And even more interesting: in collaborating with the research group of Patrick Collmbat (Université de Nice), we succeeded in creating new beta cells by activating only one specific protein in alpha cells! Application of this strategy in diabetic mice indeed resulted in the creation of new beta cells.”

Based on this more fundamental research, the next step can now be made.  Heimberg: “It is possible for patients to create beta cells themselves if they are administered the right amounts of the right medication at the right time.” In 2016, two important publications in this field appeared (of Ben-Othman and Li, both published in the journal Cell). The research group BENE of Heimberg also worked on the first publication. Heimberg: “These studies describe the discovery of a personal body signal, which can turn alpha cells into beta cells, with which diabetes can be cured in lab animals. In this experimental research, the signal was activated by artemisinin, a medicine for malaria.”

The strategy seems applicable to human alpha cells. Heimberg: “The feasibility for clinical trials are currently being investigated by our group, among others. Because a success with mice does not guarantee that it works exactly the same for humans. We need to remain careful in each step of the research. But it is in any case clear that we were able to come this far in part thanks to stichting DON and that this important support will allow us to further develop this promising research in the upcoming years.”

Prof. dr. Harry Heimberg Ph.D.

  • Researcher at the Diabetes Research Centre in Brussels and professor at the Vrije Universiteit Brussel
  • Is funded by the DON Foundation since 2012: for five years he will receive an annual amount of 100,000 EUR for research
  • Together with his research team has managed to cure diabetic mice.

Hebrew University of Jerusalem

 Aged beta cells are actually very vital insulin producers


 

A cell is like a human: it is born, grows up and eventually dies. Just like a human, a cell has its own life history, in which it develops itself at certain times and shows other behaviour at other times. You might say that Yuval Dor, diabetes researches at the Hebrew University of Jerusalem, studies the life history of pancreas cells with his colleagues.

It is easy for him to name his most important research of 2016. `That was our publication in Nature Medicine,” he says, “in which we described the results of four years of research, partly funded by DON. In it, we describe the biology of the aging pancreas cell, or, more specifically, the aging beta cell. This is the cell that produces insulin and is attacked by the immune system in the case of type 1 diabetes.”

Just like how older people can no longer produce offspring, are physically less fit and recover more slowly, aging cells divide less or barely anymore and they recover less easily when they become damaged. If this is standard for all cells, then this aging process naturally also applies to the beta cells of the pancreas, which produce essential insulin.

As we age, the division of beta cells decreases, and their efficacy is reduced. Through genetic manipulation in mice, we have managed to create a model in which a gene is activated to combat the ageing of beta cells. Surprisingly, we discovered that in response to glucose, these cells secrete more insulin than very young beta cells. Older cells may be much more effective in the event of transplants than young beta cells. These are startling results!

Professor Yuval Dor

Hebrew University of Jerusalem

But the group of Dor discovered something remarkable. The prevalent notion, that older cells (just like older humans) become less active, turned out all wrong. The researches thought up a smart trick to prove this. Beta cells can be transformed artificially into an aged situation by activating the protein p16 in the cell. When Dor and his team did so, they observed that these artificially aged beta cells in the pancreas actually started producing more insulin. When they treated mice with diabetes with p16, the mice also started producing more insulin, which improved their sugar metabolism. And activating the protein p16 in human beta cells had exactly the same effect. Dor: “We found that these older and riper beta cells showed improvement of function, instead of deterioration. That was a discovery in complete contradiction to what everybody thought at the time.”

Aged beta cells are not retired, spending their time without working, but actually the best producers of insulin. Dor: “This finding has more general biological consequences, for example for all manner of anti-aging therapies focussed on eliminating the older cells of the body. When you look more specifically to the diabetes research and the biology of the beta cell, we have moved a bit more to clinical research with beta cells created from stem cells. Hopefully, in the coming years, this research will lead to a form of cell therapy for type 2 diabetes.”

The group of Dor is currently focused on further unravelling the connection of the aging of the beta cell and type 1 diabetes. Dor: “Could those ‘aged’ cells be present in much larger amount for type 1 diabetes? Are they insensitive or more sensitive to auto-immunity, for an attack of the immune system?”

Prof. Yuval Dor

  • Professor and head of research at the Hebrew University-Hadassah Medical School in Jerusalem
  • Is funded by the DON Foundation since 2012: for five years he will receive an annual amount of 100,000 EUR for research
  • Together with his team, he is researching how insulin-producing cells grow, multiply and disappear in the pancreas

Leiden University Medical Centre (LUMC)

Embryonic development seen live


 

It is hard to imagine, but until recently we could only look into a human body by opening it up. With echo, MRI and other techniques – all relatively recent discoveries – we can already see on the outside what is going on inside.

“In 2016 in Leiden, we have – again in close collaboration with the Hubrecht Institute – opened a new window for embryonic development,” says Eelko de Koning. “We can, as explained above, minutely track the development of a single cell. But we also want to see what multiple cells do to each other during that development.”

To make that possible, a little bit of embryonic tissue can be places under the capsule of a mouse. Above that location a window is placed, giving a view of the capsule. De Koning: “This allows us to track the full embryonic development, from a few cells into whole islets. Live. We call it Intravital Microscopy. It really deals with very detailed recordings of living tissue that develops naturally right under our noses.”

My team has successfully managed to grow beta cells, but the cells are still immature. Cultivating these cells is one thing, but stopping the growth to prevent them from forming tumours, is another matter. As a result, we have not yet been successful in cultivating sufficient cells that do what we want them to do: provide the correct amounts of insulin at a given glucose value. In short, we are on the right path but we are not there yet.

prof. dr. Eelco de Koning Ph.D.

LUMC

To help interpretation of the images, they make use of fluorescent labels. “For example, we use a green colour that lights up when a cell starts producing insulin. And, remarkably, some cells do this very early on. They do not immediately produce the protein, but do produce the codes for it, which we call messenger RNA. If the RNA appears, the green colour lights up. Very interesting; you see that those cells slowly get together, start migrating and slowly form islets. That is how we can make live recordings of the origins of the islets of Langerhans.”

It is important information that, for example, supplements the analysis of the development of individual cells. De Koning: “This is a beautiful example of why this complex composition is apparently necessary to steer all those cells in the pancreas into the right development. Because cells do not follow a purely genetic development programme. On the contrary, for a large part they let themselves be steered by signals from their environment. And the signals of other cells are also part of that.”

This dynamic signalling from outside is still a large challenge to finally come to the cultivation of beta cells. De Koning: “That is a complex process. Moreover, there is also something like the blood supply, which has an important role in the body for the development of cells. At this level, too, we try to gain more clarity about what we should do to cultivate insulin-producing cells. The Intravital Microscopy can help us with that.”

Prof. dr. Eelco de Koning Ph.D.

  • Internist and endocrinologist, diabetes researcher at the LUMC and Hubrecht Institute
  • Received an amount of 750,000 EUR from the DON Foundation for his research into beta cells
  • Notable quote: “Of all the non-terminal chronic diseases, diabetes is the disease with which the patient is confronted with treatment most frequently. It has a huge impact on patients, and on their environment.”