The Open Competition ENW-XL offers funding for groundbreaking fundamental research projects set up by collaborative consortia of scientists from various universities and institutes. In this round, 21 proposals have been granted, ranging from €1-3 million per project. Here, we present those that involve members from the KNCV and/or NVBMB.  

Approaching De-Novo Life 

KNCV-member prof. dr. Sijbren Otto (UG) 
Co-applicants: prof. dr. S.J. Marrink; KNCV-member prof. dr.Anouk Rijs (VU Amsterdam); KNCV-member dr. Evan Spruijt (RU); KNCV-member prof. dr. Sabeth Verpoorte (UG) 

The researchers aim to create, for the first time, a minimal form of life from synthetic molecules. They will take a system that is able to replicate (i.e. make copies of itself) and metabolize (construct its own components from material in its environment) and make it produce its own cell-like compartments. They will then make these systems grow and divide and undergo Darwinian evolution. The research involves a collaboration between experts in chemistry, microfluidics, mass spectrometry, computer simulations, and early evolution theory. This work touches on existential questions like: “Why is there life?” and “Why are we here?”. 

HEAL-SEPSIS: a systems immunology approach for nanomedicine to heal sepsis and its long-term complications 

prof. dr. M.G. Netea (RUMC) 
Co-applicants: prof. dr. P. Pickkers; prof.dr. Y. Li; NVBMB-member dr. Roy van der Meel (TUE) 

Severe infections are sometimes complicated by complex imbalances in the way that the immune system of the patient reacts to the microbe: sometimes too strongly, and sometimes not powerful enough. The way that we should treat these infections thus depends on the type of immune regulation in each particular patient. This program will investigate how to identify the precise type of immune imbalance in each patient with a severe infection, and how to adjust the treatment in order to re-balance the host defence and improve the outcome of the patient. 

Holey trap – disordered proteins guard the gap 

prof. dr. ir. P.R. Onck (UG) 
Co-applicants: NVBMB-member prof. dr. Liesbeth Veenhoff (UG), prof. dr. C. Dekker, dr. R. Vlijm 

The transport proteins in cells are highly selective, transporting only those molecules that have precisely the right shape: structure determines function. Until recently the nuclear pore complex, a large transport system to access the cell nucleus, was the only exception to this. Its selectivity for transport arises from a unique filter system based on unstructured proteins. Now, recently, a second filter system has been found (in peroxisomes) that works similarly but at a drastically reduced complexity. In this research programme we combine biological, physical and chemical methods to use this exciting opportunity to uncover how these filters system actually work. 

Joining Forces for Human-Made Molecular Machines 

dr. ir. I. Heller (VU Amsterdam) 
Co-applicants: KNCV-member prof. dr. Ben Feringa (UG); KNCV- and NVBMB-member dr. Jocelyne Vreede (UvA); prof. dr. J. Lipfert; dr. C.P. Broedersz; KNCV-member prof. dr. Shirin Faraji (Uni Düsseldorf) 

In all forms of life, molecular motors are indispensable for transporting molecular building blocks inside cells, for maintaining DNA, and for generating (muscle-based) motion. Only recently, mankind has developed the ability to build synthetic molecular motors and machines and to control these with light. In this project, researchers from various disciplines will join forces to unravel the design-principles of synthetic nanomachines, to design motorized nanoscale building blocks and to demonstrate the first light-controlled artificial muscles and conveyor belts. These discoveries enable mankind to pursue new applications such as in nanomedicine and in the design of adaptive, mobile, and self-healing materials. 

ML-GUIDE – Machine Learning-GUIded Directed Evolution for drug discovery and (bio)catalyst engineering 

KNCV-section MCCB-member prof.dr. C. Mayer (UG) 
Co-applicants: KNCV- and NVBMB-member dr. Francesca Grisoni (TUE); KNCV-member dr. R. Robert Pollice (UG) 

Performing evolution in the test tube has proven effective to engineer tailor-made (bio)molecules that aid us in combating diseases and in realizing a sustainable economy. However, such directed evolution campaigns are slow and laborious, making the discovery of new drugs and catalysts arduous. Here, researchers will make use of cutting-edge machine learning approaches to guide directed evolution campaigns toward more effective drugs and catalysts. By melding state-of-theart techniques from molecular biology, chemistry, and machine learning, these efforts will pave the way for the out-of-the-box design of tailor-made and impactful biomolecules. 

One cell, three barrier fates – How do cereals use root barriers to survive and thrive? 

dr. K. Kajala (UU) 
Co-applicants: NVBMB-member dr. Dorota Kawa (UU); dr. V. Mironova; prof. dr. H.M. Schneider; prof. dr. J. Xu 

Cereal crops, like maize, provide most of the world’s food. However, their production is at risk from climate change, especially droughts. Our project studies how certain cells in maize roots use physical barriers to help the plant survive tough soil conditions linked with drought, such as soil compaction and presence of parasitic plants. We use advanced methods study these barriers and their genes, and test how these affect plant growth in drought. By understanding this, we can breed stronger crops that handle drought better, helping ensure food security. 

SUPerGLue: How SUbcellular ComPartments in AstroGLia control cognitive processing 

dr. M.H.G. Verheijen (VU Amsterdam) 
Co-applicants: dr. R. Min; dr. E.N.T.P. Bakker; prof. dr. H.E. de Vries; dr. P. Rao-Ruiz; dr. N.A. Goriounova; NVBMB-member dr. Harold MacGillavry (UU) 

Research on information processing in the brain previously focused mainly on communication between neurons. However, in recent years it has emerged that a non-neuronal cell, the astrocyte, which was previously seen as a kind of support cell of your brain, also plays a role in memory and cognition. Astrocytes do this by forming connections with both neurons and blood vessels in the brain. Which molecules are involved in these connections is largely unknown. In SUPERGLUE we use advanced techniques to map these molecules and cellular interactions, taking an important step in our understanding of information processing by the brain. 

Unraveling the causes and consequences of DNA damage-induced transcription stress 

prof.dr. ir. J.A.F. Marteijn (EMC) 
Co-applicants: prof. dr. M. Vermeulen, dr. H. Lans, KNCV- and NVBMB-member prof.dr. Titia Sixma (NKI), prof.dr. N.H. Dekker 

Damage in the DNA inhibits transcription of genes by RNA polymerase II, which copies the genetic information of DNA into RNA. This impediment of RNA polymerase II results in severe cellular dysfunction and accelerated aging. Through a consortium combining unique complementary knowledge and expertise, we can study for the first time the causes and consequences of DNA damage from the perspective of a single molecule to that of a whole organism. Using this approach, we will study what exactly happens to RNA polymerase when encountering DNA damage, and directly link this to the consequences at the cellular and organism level. 

Understanding the role of myeloid cells in cancer immunotherapy failure or success 

prof. dr. S.H. van der Burg (LUMC) 
Co-applicants: dr. M-P. Chien; NVBMB-member dr. Tineke Lenstra (NKI); prof. dr. K.E. de Visser; dr. S. Derks; dr L. Akkari; prof. dr. I.J.M. de Vries; prof. dr. L. Meyaard     

Current cancer immunotherapies activate the immune system to fight tumors but are effective only in some patients. Certain types of immune cells, called myeloid cells, can impact treatment success by either helping or hindering immunotherapy. We aim to understand which myeloid cells are crucial for successful treatment; when and how these cells interact with each other and with the tumor; what are their roles in the tumor and in response to treatment; and how to use machine learning to predict treatment responses. By studying this, we will improve our understanding of myeloid cells in cancer treatment effectiveness and tumor control. 

Viruses like it sweet; virus-glycan interactions as determinants of host range and pathogenesis 

dr. D.A.J. van Riel (EMC) 
Co-applicants: dr. M. de Graaf; dr. R.P. de Vries; KNCV-member prof. dr. Geert-Jan Boons (UU); dr. B.L. Haagmans; dr. K.R. Reiding; dr. L. Bauer 

Viruses cause a significant disease burden in both animals and humans, often using sugars to bind to cells before infection. The ability of a virus to infect a host, as well as the specific organs it can target and its pathogenicity, is influenced by the repertoire of sugars expressed by the host and the virus’s ability to bind to these sugars. We aim to understand virus-sugar interactions within the respiratory and gastrointestinal tracts, as well as the central nervous system. Our findings will inform surveillance strategies for potential zoonotic viruses and enhance public health risk assessments. 

Open Competition ENW-M 

The Open Competition ENW-M is geared towards funding relatively small, creative and high-risk research projects that could develop into new research themes for the future. In this round, 23 proposals were granted, including three submitted by KNCV- and/or NVBMB-members. 

Next-Gen? Coll-a-Gen! 

KNCV-Section Organic Chemistry-member dr Jordy Saya (UM) 
Collagen is a crucial protein that provides strength and support to various biological tissues, including bones, skin, and cartilage. However, obtaining collagen from animal sources presents challenges such as potential disease transmission and variable quality, whereas synthetic production methods often struggle with low yields and high expenses. This project introduces a new, efficient way to generate collagen-like materials using Ugi polymerization, aiming for scalable and eco-friendly alternatives. Success in this initiative could revolutionize medical treatments, from advanced wound healing to biocompatible implants, enhancing patient care and environmental sustainability. 

How does USP7 select its targets 

KNCV- and NVBMB-membr prof. dr Titia Sixma (NKI) 
Here we study the regulation of USP7 to understand when and where it is active. We use a combined chemical and biochemical approach to create stable USP7 activation states in vitro. We will use biochemistry, structural biology and proteomics to analyze changes in activity, structure and interactome. This will give insight in the regulation of the crucial signalling enzyme. 

Bringing ancient proteins to life: Was everything once better than today? 

KNCV-member prof. dr Marcellus Ubbink (UL) 
Based on the amino acid sequences of protein families, those of their ancestors, of hundreds of millions of years ago, can be reconstructed and analysed. In this project laboratory evolution will be performed on these ancestral proteins to determine what happens to their extraordinary properties when they evolve to be more similar to their modern counterparts. Do they become less stable and does their activity change? These insights will contribute to the design of new enzymes for human applications.