Chemistry as the key to medical innovation
Is it a coincidence that three chemists from the same department have each independently received a ZonMw grant? 'No,' the researchers agree in unison. 'The role of chemistry in medical biology is becoming increasingly important, and we’ve worked hard to make this happen.'
In this round of the ZonMw Open competition, research teams were asked to propose initiatives that contribute to the advancement of fundamental biomedical science and healthcare innovation. Sander van Kasteren, Madeline Kavanagh and Kim Bonger will receive over €800,000 in funding separately, but together with their research team. Van Kasteren says: 'The fact that three projects from our institute were separately awarded is definitely a milestone we can be proud of.'
Leiden as a chemical biology and drug discovery hub
Madeline Kavanagh joined the faculty in January of last year. Originally from Australia, she chose Leiden because, in her view, few chemistry departments are as invested in interdisciplinary and translational research as Leiden. ‘My research combines chemistry, biology, and advanced technologies (like mass spectrometry) to study disease and develop therapeutics. Therefore, it is essential to have access to all these facilities, which is uncommon in traditional departments.’
But more importantly says Kavanagh: it is about the people. ‘In Leiden, we can easily collaborate with researchers in other institutes, like biology, and the medical center, which was critical to putting together our ZonMw proposal. Fostering interactions between researchers from different fields helps spark new ideas. I often find we are interested in similar biomedical questions, but have different perspectives and skills that when combined, can help us come up with exciting solutions.’
‘We've often told our story in immunology and biology departments and at conferences, essentially giving chemistry lectures. The power of repetition has worked.’
Understanding diseases and developing treatments
Sander van Kasteren has been a professor of Molecular Immunology at the faculty for 12,5 years. His research focuses on the molecular workings of the immune system, and together with Kim Bonger, the three form a perfect complement to one another. 'We share a very similar vision,' explains Van Kasteren, 'namely that chemistry is of great value in medical biology. We look at how molecules interact with biology on a molecular level. This way, we can better understand the foundation of various diseases and, in turn, develop treatments and therapies. Our role as chemists in medical biology is growing, but we and a lot of other researchers had to work hard to get here.'
Van Kasteren compares this to starting a band where no one listens at first. You can play whatever you want, but there’s no audience, and you’re certainly not going to have a hit. But slowly, people begin to listen. 'We've often told our story in immunology and biology departments and at conferences, essentially giving chemistry lectures. The power of repetition has worked. We’re here to help. We’re being asked more and more to share our thoughts or speak. For example, Kim is currently in Italy speaking at a conference and I am speaking again as a chemist on a immunology conference next month.'
LED3 Network: Biology, Chemistry, and Drug Development
With the arrival of Bonger and Kavanagh at the chemistry institute and the focus on immunology, it was decided to create a new division: Chemical Biology & Immunology. Kavanagh: 'This allows us to combine our strengths, knowledge, and networks.' This also aligns with the LED3 network, which stands for Leiden Early Drug Discovery & Development. It is a collaboration between the Biology, Chemistry, and LACDR institutes. Kavanagh and Van Kasteren explain: 'This way, we can rely on a large group of experts we work with. New collaborations are forming, we’re holding networking events, and we’re putting ourselves on the map.'
The proposals
Chemical Approach for Immune Inhibitory Receptor Agonists
Prof. L. Meyaard, UMC Utrecht, Prof. S.I. van Kasteren, Leiden University, Dr M. van der Vlist, UMC Utrecht
Immune-mediated inflammatory diseases (IMIDs) affect 5–7% of the Western population. IMIDs comprise a chronic, clinically diverse group of conditions and many patients still lack good treatment options. Stimulation of immune checkpoint receptors is a novel strategy to suppress inflammation in IMIDs. Development of therapeutic checkpoint stimulators to suppress inflammation is challenging. In contrast to most receptors, scientists do not understand how the concentration or binding strength of natural stimulators affects these checkpoints. With a recently developed microscopy technique and a unique set of checkpoint receptor binders, we will study the detailed characteristics of binder:receptor interaction that determine immune checkpoint function. With this knowledge, we aim to chemically synthesise checkpoint stimulators for future therapeutic use in inflammatory disease.
Targeting lipid metabolism to develop host-directed therapeutics for mycobacterial infectionsProf. H.P. Spaink, Leiden University, Dr M.E. Kavanagh, Leiden University, Dr A. Saris, Leiden University Medical Center, Dr W. Hoefsloot, RadboudUMC
Mycobacteria have killed more people in history that any other infectious disease. Treatment involves taking multiple drugs over many months, and usually results in toxic side effects. In addition, the mycobacteria are becoming increasing drug-resistant and we have no effective vaccines. Our research aims to develop drugs that boost the host immune response to better defend us against mycobacteria. Specifically, we are targeting the metabolisms of fats, which are important molecules regulating immunity. These “host-directed therapies” should be effective against antibiotic resistant infections, and could work in combination with existing drugs to reduce side-effects and shorten treatment times.
Novel CAAR-T cell strategy to tackle complex autoantigen-driven autoimmune diseases
Prof. M.H.M. Heemskerk, Leiden University Medical Center, Dr K.M. Bonger, Leiden University, Dr M.G. Huijbers, Leiden University Medical Center, Prof. H.U. Scherer, Leiden University Medical Center, Dr J.M. Weber, Delft University of Technology
Most human autoimmune diseases (AIDs) are chronic conditions without a prospect of cure. The advent of Chimeric Antigen Receptor (CAR)-T cell therapies marks a groundbreaking advancement in cancer treatment. First results using CAR-T cells in B cell mediated AIDs now also show highly encouraging, potentially curative effects. However, such therapies indiscriminately target all B cells which leaves patients vulnerable to serious infections. In contrast, precise immunotherapies that specifically target pathogenic B cells while preserving healthy ones offer a promising avenue for safely managing and curing AIDs. Chimeric Auto-Antigen Receptor-T cells (CAAR-T cells) provide a platform capable of antigen-specific B cell targeting. Here, we aim to develop a novel approach to selectively target pathogenic B cells to such autoantigens allowing their selective killing by redirected CAAR-T cells in AID patients.
Read more about the proposals here.