Biodegradable patches for children with congenital diaphragmatic hernia
From bench to bedside, a small step in cardiology?
The search to improve the conditions of the CAH patientI’ll do research as long as there are unanswered questions
Clinician and pediatric endocrinologist Hedi Claahsen has had an eventful year. Besides her ongoing research and clinical work, one of her papers published in a high-impact journal* won the Dietrich-Knorr Prize for the best-2019 paper in the field of adrenal research. With the opening of the Radboud center of expertise Sex & Gender and the hosting of the first international CAH symposium, it doesn’t seem like things are going to calm down any time soon.
You’re considered one of the leading experts in the field of Congenital Adrenal Hyperplasia. Can you briefly explain this condition and your research?
“Congenital Adrenal Hyperplasia – CAH – is a group of inherited disorders affecting the adrenal glands. The adrenal glands produce corticosteroids and sex hormones (androgens). CAH patients don’t produce enough corticosteroids, which play a role in blood sugar levels, blood pressure, and the immune system. Due to a lack of the cortisol driven negative feedback system, the adrenal glands are continuously stimulated, becoming bigger (hyperplastic) and produce high amounts of adrenal sex hormones. In female CAH patients, the elevated androgens lead to prenatal virilization of the external genitalia. With medication like hydrocortisone, the missing corticosteroids can be replaced, and androgen production will be suppressed."
“One of my research themes is long-term complications in CAH patients. Male CAH patients have a high risk for infertility due to the presence of benign tumors growing in the testes. These tumors are known as testicular adrenal rest tumors, also known as TARTs. We discovered that these tumors seem to have features of the adrenal gland tissue. Our current study also shows testicular features. We, therefore, hypothesize that TARTs consist of more totipotent cells, such as embryological tissue. Now, our research focuses on the cause of tumor growth. This knowledge will hopefully help to develop medication to treat or prevent TART and, consequently, improve fertility."
“Another research line is carried out in close collaboration with Dr. Agustini Utari from Diponegoro University in Semarang, Indonesia. In Indonesia, medication, such as hydrocortisone, is not readily available. We know that untreated patients with adrenal diseases and cortisol deficiency have a high mortality rate. However, we observed that some CAH patients with severe cortisol deficiency still survive without medication. How is this possible, we wondered? We were able to show that these patients do have deficient cortisol production but strongly elevated precursor hormones that typically accumulate in CAH patients. Our in vitro studies showed that these precursors have similar cortisol activity on the glucocorticoid receptor and may probably partly compensate for the lack of cortisol. We still collaborate with Indonesia and hope to learn more about the natural course of this disease, and to improve medical care for these patients.”
You combine clinical work with research. Was it always your ambition to do both?
“I started my career as a children’s nurse at a local hospital in Germany. But I soon realized that I wanted to learn more, so I began studying medicine in Nijmegen. After completing my medical degree, I started my training as a pediatrician and pediatric endocrinologist and began my clinical PhD research on TARTs."
“Every day, my colleagues and I deal with unsolved clinical problems. With my research, I try to advance medical care, improve my patients' quality of life, and prevent long-term complications. As long as there are unanswered questions, there’s a reason to continue our research."
You have two exciting events coming up: the opening of the center of expertise Sex & Gender and an international symposium. Can you tell us a little about them?
“I’ve been the coordinator of the Radboud DSD center – Disorders/differences of Sex Development – for several years now. There’s a considerable waiting list for transgender patients. Our center has a highly dedicated DSD team, which consists of, for example, specialized nurses, endocrinologists, psychologists, and urologists. We realized they all have the necessary knowledge needed to offer transgender care. So, we decided to expand the center to Sex & Gender. I want the center not only to be a clinic where we help patients individually but also where we can pursue interesting new research themes as many transgender-related questions are still unsolved."
“Officially, the Radboud expertise center Sex & Gender will open in March 2020. With a skilled multidisciplinary team, we’ll offer highly specialized care and guidance to people with gender dysphoria. But, of course, we’ll continue our current care for people with variations in sex development.
“In October 2020, Radboud University will host the first international CAH symposium. I'm very excited to chair this symposium. Experts from all over the world accepted our invitation to come to Nijmegen and to discuss their current research in the field of CAH."
“The involvement of patients is important in both my clinical work and my research. For the implementation of the center and the upcoming symposium, we asked for input from patient organizations. They give us their views on varying aspects of our clinical care and our research questions. We also ask them to give their views on our grant proposals. I think this collaboration is one of our strengths. In March, our team will organize the annual CAH-day for the fifteenth time. Our patients and families get the opportunity to meet and to learn about the latest news in CAH care and research. It's an event we enjoy; and we get a lot of positive feedback and suggestions."
You sound extremely busy. How do you do it all?
“My days are certainly full. But my enthusiasm drives me. I enjoy my work every day. And working with my team and within my networks is a great pleasure for me."
"Of course, nothing's self-evident; I manage a lot of tasks myself. For example, I sometimes work deep into the night, writing a grant proposal. I also take the initiative for new endeavors. I like approaching people, and I've found that I'll always meet professionals who want to discover what we can achieve for our patients together."
*Journal of Clinical Endocrinology & Metabolism
Publishing your research; what is happening afterwards?I was surprised by how many people actually read it
PhD candidate Suraya Elfrink saw the research she conducted with Lotte de Winde and Michiel van den Brand published in Blood. Together with her supervisor Annemiek van Spriel, Suraya reflects on her research and the impact of being published.
Can you tell me a little about the research that was published in Blood, the journal of the American Society of Hematology?
Suraya: “Tetraspanin CD37 is frequently mutated in patients with diffuse large B cell lymphoma (DLBCL) occurring at immune-privileged sites. The CD37-mutated lymphoma B-cells show impaired CD37 cell surface localization, which has important implications for anti-CD37 immunotherapy. In other words, this study provides novel molecular insight into DLBCL at immune-privileged sites. It indicates that CD37-based therapies are more likely to be beneficial for DLBCL patients that harbor no CD37 mutations.”
Annemiek: “It’s, therefore, predictive for DLBCL patients who do have CD37 mutations as they don’t need to undergo the expensive and evasive anti-CD37 immunotherapy because we know that it will not help them. Practically, it means they can spend their time and energy on another treatment that will hopefully have a positive effect."
What is it about research that attracts you to do it Suraya: the fundamental questions or the possible impact on patients?
“I certainly like the fundamental questions,” says Suraya, "but I also see the personal picture concerning my research. I genuinely understand the impact of it. As a child, I always saw myself as an archeologist or perhaps a historian. Then I got cancer when I was around 13 years old. In eighth grade, you have to choose your subject package, and due to my illness, I decided to take subjects like Biology instead of History. I’ve never regretted that choice.
“I was treated right here at Radboudumc. One of the oncologists who treated me still works here. He knows I’m doing research as he saw an article about me on the back of the Radbode. He once asked how my PhD was going, and I’ll definitely send him my thesis when it’s done.”
Blood – which is a prestigious journal – published your PhD research. How did it come about, and what did getting published mean to you?
Suraya: “Annemiek and I submitted the article to Blood together. It was my first time submitting an article. I remember we sat behind the computer for 3 hours or something. I was yelling at the computer because technically things weren’t going the way they should. But Annemiek stayed remarkably calm.”
Annemiek: "Writing the article went smoothly. Blood was the first journal she submitted to, and after it was accepted, she revised the manuscript herself. I was so proud of her. She'd worked exceptionally hard. I enjoy working with PhD candidates: watching them work and develop into independent researchers. "
Suraya: "I understood that getting published in Blood was an accomplishment, but I didn't realize how big until the magazine came out, and people started congratulating me. I was surprised by how many people actually read it."
You do research independently, but how is the support within the research group?
Annemiek: "Our team consists of about ten people and includes postdocs, PhD candidates and Master's students. Everyone works hard and is motivated not just by their personal research but also each other's."
Suraya: “We’re a close team. There’s definitely no animosity. We all want to get published, and we help each other to get there. All successful publications are celebrated equally: there's no ranking. We have a 'Wall of Fame' within the Tumor Immunology department. When someone gets published, we post the article on that board. After ten posts, we have a drink together to celebrate as a department.
“Of course, getting published isn’t the most important thing. It’s about growing as researchers. We’re all passionate about our work. And our goal is to become independent researchers under Annemiek’s supervision. In the team, we can share our successes and our frustrations. We help remind each other that the failed experiments and annoying reviews will be worth it in the end.”
Annemiek: "I think the most important thing for research is to love what you do. Find a research topic that excites you. Then you don't have to stress."
Suraya, smiling: “Although you will be stressed!”
Annemiek, smiling too: “Yes, but you shouldn’t start off being stressed.”
What are your plans Suraya? Remain in research or do you have other ambitions?
Suraya: "I hope to get a postdoc position somewhere in the field of oncology, preferably in pediatric oncology. I want to go somewhere outside of the Netherlands. It would be useful to establish myself in a different environment and learn from that as well.
“I consciously chose not to work directly in the clinic. Considering my background – my ‘role as survivor’ – that would be too personal. Although, I do like reading stories about patients, via, for example, patient organizations. I enjoy the connection; it keeps me aware of what I'm doing it for.”
STORMy discoveries by our cell biologists
Veni grant from NWO for Anat Akiva, Rob Arts, Martijn van den Bosch, Jitske Jansen and Annie YangCan’t remember ever being as nervous as I was for my Veni defense
With five NWO Veni grants being awarded to RIMLS this year, the institute was generously rewarded. Four Veni awardees came together to discuss their research, their Veni grants, and their research careers.Who are this year’s 250 kEuro Veni awardees, and what are they researching?
Rob Aarts is the only Veni awardee this year who works part-time in the clinic as an internist in training. His research focuses on the memory of the innate immune system and the role of the anti-inflammatory cytokines interleukin-37 and IL-38.
Jitske Jansen was awarded the Veni grant to study kidney regeneration after acute kidney failure. Her aim is to elucidate molecules secreted by immune cells and pericytes that are essential for successful for kidney epithelial repair.
Martijn van den Bosch focuses on osteoarthritis and aims to unravel the inflammatory mechanisms that drive the osteoarthritis pathology, which might be used to develop disease-modifying therapies.
Annie Yang is looking into the complex life cycle of parasites in hepatocytes during malaria infection. Back in Melbourne, she had already begun researching the liver stage of the malaria parasite. She moved to Nijmegen because of Radboudumc’s strong history in malaria research, especially in terms of innovation.
Anat Akiva also obtained a Veni grant. She was working in Eindhoven and brought the grant with her when she transferred to Radboudumc. Her research focuses on biomineralization, aiming to understand the processes of hard tissue formation in health and disease.
Were you confident the committee would award you the grant?
Jitske: “I can’t remember ever being as nervous as I was for the Veni defense. It was basically a go or no-go for my research career. It was the final time I was permitted to apply, considering the time constraints of application – no more than three years after completing your PhD. I needed the money to be able to continue in research, which I'm passionate about. The Veni will pay for my income in the coming years, but I'll need more financing to be able to achieve everything I want with my research.”
Rob: “I also had my medical career and other grant applications if I didn’t get the Veni, so not super nervous. Of course, getting a personal grant is so much nicer and gives you more freedom. I want to combine the clinic and research. Attaining a Veni grant is a significant first step to becoming a researcher.”
Annie: “I was surprisingly relaxed for my defense. I knew someone else from my department (Medical Microbiology) was also applying. The chance of both of us getting a Veni grant was very slim. I, therefore, lowered my expectations and also concentrated on getting other grants. It was also nice that I saw my mentor just before I went in. She gave me a word of encouragement, which calmed me down.”
Martijn: "For me, it was the second time applying for the Veni grant, and, like Jitske, it was my last chance to get it. However, as I’d done a defense the year before, I knew what to expect. I was more nervous the first time. Whereas the first time the questions sometimes took me by surprise, I was now totally prepared.”
Do you have tips for PhD candidates considering a career in research?
Martijn: "Choose a topic that truly interests you. No grant application is easy. There are multiple rounds, and I'm sure that if you're not motivated enough, the committee will soon filter you out. It would help if you also took a chance with your topic. Remember: mid-risk means mid-gain."
Annie: “I noticed that the difference between criteria in Australia and Europe is that here they’re looking for more out-of-the-box ideas. In Australia, you almost have to have proven your hypothesis before you get funding. I found my research topic because I kept waiting for someone else to solve an issue that stagnated my research. I scanned all the literature, but the answer never came. So, I decided to solve the problem myself.”
Jiske: “Start with the patient. How could you solve a particular problem they face? It might also be useful to look at the 'front end.' For example: successfully regenerating the kidney after acute renal failure might possibly prevent the progression to end-stage renal disease and the need for dialysis treatment. Also, start writing your proposal on time!"
Rob: “My research is fundamental, yet as it has to do with the immune memory system, it's also applicable to many diseases. That may have helped to get the grant. I think it also helps if your research is a logical next step after your PhD research. That you have the necessary background."
How was the support from RIMLS in trying to attain these national grants?
Rob: “I believe the success rate of awarded Veni-Vidi-Vici grants is a bit higher for Radboudumc than other medical centers.”
Martijn: “I heard that too. I think their pre-selection has a lot to do with it. We have to hand in our proposals to Radboudumc’s Grant Support Office in May. It makes you think about your research a lot.”
Annie: "They expect you to come up with something novel. There are several rounds, discussing your ideas back and forth. The process forces you to think about things, giving you enough time to work out your topic.”
Jitske: “They also help prepare you for what’s to come during the grant application: writing proposals, rebuttals, and interview training.”
Martijn: “It also helps that many PI’s at Radboudumc have also gone through the Veni-Vidi-Vici review process. They know from experience what questions could come up and can help prepare you through mock interviews."
Annie: “RIMLS’s orientation is horizontal. Supervisors include you in their grant applications for bigger projects. You have brainstorm sessions together, and they send grant proposals to everyone on their team for feedback. It teaches you things for your own grant proposals."
Rob: "You're truly part of a team here. And you can ask help from anyone, whether it's another PhD candidate also applying, or a technician or a PI. Everyone is committed to research."
The year of Daniele TaurielloBig ambitions with miniature tumor models
Last year, Daniele Tauriello was awarded an NWO/ZonMW Vidi grant as well as Radboudumc’s Hypatia grant for research group leaders. These grants have allowed him to start an independent group. Now, he can continue his research into restoring the immune system to prevent cancer from spreading.Can you tell us a bit about the research you’re doing at RIMLS? I believe, it’s related to the postdoc research you did in Barcelona.
“In 2011, I began investigating colorectal cancer (CRC) metastasis at the Institute for Research in Biomedicine (IRB Barcelona). The aim was to generate a better model, with an intact immune system. My colleagues and I created a metastatic mouse model that recapitulated just about all the relevant characteristics of human CRC with poor prognosis. I then put the tumors generated by our new model into culture as organoids."
“Successful reimplantation (in mice) of those organoids was vital in the development of new insights on immune suppression in liver metastasis, leading to a promising new treatment option. The future, I think, lies not in merely killing the cancer cells directly, but rather in treating the whole tumor ecosystem."
“So, with the mouse tumor organoids I generated in Barcelona, I now want to look at an earlier point in time in metastasis—when these lesions are still undetectable and, presumably, either biding their time or struggling to grow out. We’ll model the tumor microenvironment of these early lesions in cell culture conditions.
“Next, we'll make patient-specific in vitro models to gain more understanding of the cell-to-cell communication responsible for immune evasion and tumor metastasis. At least in principle, we could then develop and test bespoke therapies for a given patient. The idea is that if we can stop the tumor early, we can prevent metastatic outgrowth, which, of course, is better than having to cure it.”
Why conduct this research at Radboudumc? Were you confident that you would be able to secure grants by associating with RIMLS?
“For personal reasons, I wanted to come back to the Netherlands. More than any other institute I considered, I found both a strong match of scientific interests and facilities and a supportive atmosphere. The new rules for the Vidi grant mean that before you can apply, you need an embedding guarantee from a Dutch institution where you intend to conduct your research. With the help and support of researchers at the departments of cell biology and tumor immunology, I was able to write my proposal and secure the grant."
“As for the Hypatia grant: I believe I owe this opportunity in part to the same supportive researchers, lobbying on my behalf. I’m very grateful for this. Getting both grants gives me the means to provide an income for myself and a team of researchers to work on this ambitious project and develop other clinically-oriented projects as well.”
You’ve now been in Nijmegen for several months. Are you satisfied with your choice to come work at RIMLS?
“Yes, definitely. Very early on, I met Henk Verheul – professor in medical oncology – who moved to Nijmegen the same time I did. Although we work in different departments, we discovered that our research is highly complementary. I concentrate in the pre-clinical setting with translational ambitions, and he works in the clinic, in need of more fundamental research partners. It's great to bounce ideas off each other and collaborate.
“I also started a translational CRC research alliance together with Nielka van Erp – associate professor at the pharmacy department – and Iris Nagtegaal – professor of gastrointestinal pathology – to address urgent clinical problems and bring novel therapies to patients."
“But that’s not all. There's also Annemarie Boleij from the pathology department with whom I’ll study the role of microorganisms in metastasis. And with associate professor in translational immunohematology, Harry Dolstra, we're already studying a new immunotherapeutic option for patients with metastasis. And I've not even mentioned the collaborations within the departments of cell biology, tumor immunology, and other RIMLS groups. The open and positive atmosphere at the institute is exceptional and has made my start both pleasant and exciting."
What are your ambitions for your research and your career?
“I want my research to impact the lives of people with cancer. The hope is not only to prolong the lives of patients but also to prevent metastatic suffering, and reduce treatment toxicity. It may sound very ambitious, but I’ve three reasons to be optimistic: an increasingly effective handle on cancer drivers, an upsurge in the field of immuno-oncology, and the emerging insight of the tumor ecosystem to guide treatment combinations."
“I started by carefully setting up a team for my lab. I think it's crucial to find qualified candidates that not only complement one another but also work well together. As group leader, I'm responsible for the team: their growth as researchers as well as the collective atmosphere. I need researchers who can work independently on problems that will later come together in solving more complex puzzles. Good science requires people with expertise who are willing to share their pragmatic creativity."
“I feel confident I have the ingredients to build an outstanding research line."
Daniele Tauriello was one of three researchers at RIMLS who was awarded a Vidi grant in 2019. Who are the other Vidi awardees, and what research are they doing?
Mathijs Jore works at the Department of Medical Microbiology, and his research focuses on malaria. His fundamental research looks at how malaria parasites can evade the human immune system at a molecular level. The aim is that the acquired insights will be used to develop novel drugs and vaccines against malaria.
Johannes Textor is looking into how intelligent our immune system is, at the department of Tumor Immunology. He will train computer models of the immune system to recognize text and images to understand how the system learns, forgets, and gets confused. This will help to design therapies that use the immune system, such as vaccines.