Twenty-eight promising research projects launched within Open Competition ENW-XS

Gele luchtballon tegen blauwe lucht boven veld met gele bloemen.

The NWO Domain Board Science has awarded 28 applications in the Open Competition Domain Science - XS. The topics range from the Asian tiger mosquito to the creation of a magnet and tiny vesicles as information carriers.

The awarded applications (in alphabetical order of applicant):

Shaping the blood brain/tumor barrier using light.
Dr. A. (Angelo) Accardo (Delft University of Technology)
The blood brain barrier (BBB) plays a crucial role in various neurological diseases (e.g., brain tumors, Alzheimer’s, multiple sclerosis). Although its selective permeability is vital to preserve brain functions, it also hinders the diffusion of drugs to their targets. To date, there is not a 3D model of the BBB, which holistically incorporates its geometric, biochemical and flow features. We will pioneer this model by combining cell-culture with laser-assisted 3D printing and microfluidics, and apply it to patient malignant brain cancer (gliomas). The results will pave the way for the assessment of glioma treatments (e.g., drug delivery or immunotherapy).

Observing the birth of a magnet in real time: ultrafast emergence of spontaneous magnetic order in van der Waals magnets.
Dr. D. (Dmytro) Afanasiev (Radboud University)
Understanding how magnetic properties of matter emerge when atoms are brought together has challenged people’s minds since ancient times. Inspired by the fact that magnetism cannot exist in 2D, we propose an experiment to answer this monumental physics question by observing the birth of a magnet in real time. Using so-called quasi-2D van der Waals magnets, that become 3D under high pressure, we will employ a pressure cell to bring the magnet to the verge of the 2D→3D crossover and then kickstart it towards the new dimensionality using a femtosecond flash of light capturing the fundamental dynamics of magnetic ordering.

SmartComplete: an ultimate approach for analysing complete transcriptomes, from bulk samples to single cells.
Prof. dr. E. (Eugene) Berezikov (University Medical Center Groningen)
Next-generation sequencing of RNA is now an integral part of nearly every genetic study where gene expression levels are relevant. Yet methods to generate libraries for RNA sequencing still need improvements in sensitivity, transcriptome coverage and costs. Here we propose a new approach, SmartComplete, which can simultaneously analyse the complete transcriptome of a cell, including messenger RNAs, non-coding RNAs and short RNAs, in a single one-pot library preparation, and at greater sensitivity and a fraction of costs of commercial kits. Once fully optimized, SmartComplete is poised to become the method of choice for all RNA sequencing applications.

Cancer-associated fibroblast subtypes: who does what?
Prof. dr. A. (Alessandra) Cambi (Radboud university medical center)
Solid tumours hijack neighbouring healthy cells to create environments that help tumour growth and spreading. Fibroblasts are cells that are present in all our organs and can be manipulated by the tumour. We know that these cancer-associated fibroblasts come in many types: some produce collagen and facilitate tumour invasion, others secrete molecules that fool the immune system helping tumours to escape. We do not know, however, the specific functions of these different types of fibroblasts. Here, we will develop new, reproducible and standardized procedures to induce these different fibroblast types in the laboratory to better understand their role in cancer.

What limits mitotic checkpoint signaling in the early embryo?
Dr. J.L. (Julia) Kamenz (University of Groningen)
Cell division is a fundamental process, which allows a single fertilized cell to develop into a complex organism containing trillions of cells. Errors during cell division can have detrimental consequences, such as birth defects or cancer development. To prevent errors, molecular surveillance mechanisms, so-called cell cycle checkpoints, tightly monitor and regulate cell cycle progression. Surprisingly, cell cycle checkpoints are largely absent during the early embryonic divisions. In this XS project, we aim to prove or disprove the hypothesis that the extraordinarily large volume of the early embryonic cells constitutes a fundamental biophysical limit to functional checkpoint signaling.

Changes in brain DNA: Identifying RNA-templated DNA repair in human neurons.
Dr. J.A. (Juliette) Kamp (Erasmus Medical Center)
To stay healthy, cells must repair their DNA. In most cells, DNA damage is preferentially repaired using a DNA-template to avoid mutations. However, neurons are thought to rely exclusively upon error-prone non-templated repair due to lack of a DNA copy synthesized during cell division. Because DNA is transcribed into RNA, we hypothesize RNA provides an alternative repair-template. Polymerase theta was shown recently to generate DNA from an RNA-template in dividing cells. We will investigate if polymerase theta enables RNA-templated repair in human neurons, giving insight into the occurrence of (harmful) mutations and feasibility of therapeutic gene editing in the brain.

Nightshift CAR-T Cells.
Dr. W. (Waleed) Kholosy (University of Amsterdam)
Modifying T lymphocytes to express chimeric antigen receptors (CAR-T), empowers their ability to recognize cancer antigens and eliminate cancer cells. A major mechanism of CAR-T cell therapy failure is the functional exhaustion of CAR T cells, which get overwhelmed by constitutive CAR-mediated activation and a prolonged exposure to cancer antigens. Here, I propose a strategy to maintain CAR-T cell fitness by engineering them to work in nightshifts. Melatonin, a hormone released during night, will orchestrate nocturnal CAR expression, allowing intermittent activation and resting periods due to transient cessation of CAR signaling during the day, resulting in fitter CAR-T cells.

Cell-cell communication as basis for improved multiple sclerosis patient stratification.
Dr. G. (Gijs) Kooij (Amsterdam University Medical Center)
Multiple sclerosis (MS) is a chronic neuro-inflammatory disorder mainly affecting young adults in their prime of life. In order to improve diagnosis, there is a high and unmet need to define blood-based tests that use individual or biomarker panels to revolutionize patient stratification and enable personalized treatment regimens. For that, we here focus on blood platelets (BPs), that have been recently shown to contain different communication molecules, such as RNA and lipids. We here aim to decipher such cellular communication signals to not only provide novel ways to diagnose and stratify patients, but also to potentially steer detrimental immune responses.

Light-activated therapeutic nano-transformers for treatment of triple negative breast cancer.
Dr. H.T.D. (Duc) Le (Eindhoven University of Technology)
Triple negative breast cancer is an aggressive subtype which is difficult to treat. One of the promising drug candidates is a cytokine namely TRAIL which can specifically activate cell death signalling on cancer cells but not on healthy cells. Multivalent TRAILs need to be displayed on a nanocarrier to facilitate signalling; however, current state-of-the-art nanoplatforms have limited tissue penetration because of their size. Here, we will develop a biopolymer-based nano-transformer displaying TRAILs, which decreases its size upon light activation to afford better penetration and improved therapeutic efficacy.

It’s all in the genes: Seed dormancy depth as a predictive indicator for abiotic stress resilience in plants.
Dr. H.A.C.F. Leeggangers (Utrecht University)
With climate change threatening food security, there is a high demand for developing climate-resilient plants. To accelerate this elaborate breeding process, the development of predictive indicators for stress resilience is essential. A potential predictive indicator is the hibernation depth of seeds, which unexpectedly shows a relationship with the level of flooding resilience. In this project, I will explore the relationship between seed hibernation depth and environmental stress resilience, and its potential to become a predictive indicator. When successfully validated and commonly observed between multiple stresses, the road is paved towards developing new strategies to breed climate-resilient plants.

HIGH TIME – High resolution insights into transcriptional immune responses in mosquito gut explants.
Dr. P. (Pascal) Miesen (Radboud university medical center)
The Asian tiger mosquito (Aedes albopictus) is an invasive species that transmits important epidemic viruses such as Chikungunya virus. When mosquitoes take a bloodmeal on an infected individual, viruses first need to infect and replicate in the midgut, the mosquito’s equivalent of a stomach. If this infection is inefficient, further infection of the mosquito cannot proceed and virus transmission is blocked. In HIGH TIME, the researchers investigate the first cellular responses to virus infection in the mosquito midgut to better understand the mechanisms that determine whether infection can be established and ultimately transmitted to a human host.

Viral neurodegeneration:viral infections as triggers of peripheral neurogenerative disorders.
Dr. N. (Natalia) Mora Garcia (Donders Institute for Brain, Cognition and Behaviour, Radboud University)
Peripheral neurodegenerative disorders are a large cause of mortality. Although the genetic contribution is known to be high, the genetic cause for a large number of patients remains unknown. One factor complicating the identification of diseasemutations is incomplete penetrance, where the disease only develops in combination with an environmental factor. One such factor may be viral infection. While viruses can stimulate many pathways implicated in neurodegeneration, it is unclear if infections are merely a confounding factor or causally linked. To understand the role of viral infection, we are using Drosophila to investigate how it affects neurodegeneration in genetically susceptible individuals.

In search of a Super Hero Protein.
Dr. S. (Stijn) Mouton (University Medical Center Groningen)
Most proteins require correct folding to function. Misfolded proteins can aggregate, causing disease. Interestingly, also unfolded, disordered proteins exist, called Hero proteins in humans. Hero proteins help preventing pathogenic aggregation, but while each Hero protects some proteins, it can also drive aggregation of others. This project aims at designing Super Hero proteins which protect multiple proteins without negative effects. For this design, we will identify and characterize Hero proteins in diverse animals. Candidate Super Hero proteins will be validated by expressing them in yeast and worm-models of neurodegenerative disease to test if they can reduce aggregation and improve health.

Phage pool party – fighting antibiotic-resistant infections with a carefully chosen virus.
Dr. Y. (Yuval) Mulla (Free University Amsterdam)
Antibiotic resistance is on the rise. Bacteria-killing viruses (phages) are a promising alternative to combat resistant infections. Unfortunately, whereas antibiotics have a broad spectrum for many species of bacterial pathogens, phages are highly specific. Therefore, every patient requires testing of many phages to find a candidate suitable for therapeutic use. With current methods, this often requires more time than a patient can afford. Here we propose a novel method where we pool many phages together in a single test and find successful candidates via rapid, third-generation sequencing. This quick screen will allow a precision medicine approach to phage therapy.

Is there a molecular connection between acute myeloid leukaemia and nuclear transport?
Prof. dr. ir. P.R. (Patrick) Onck (University of Groningen)
Acute myeloid leukaemia (AML) accounts for approximately 80% of all cases of adult leukaemia, with poor success rates for current treatments. Recently, a wide proteomic screening showed a remarkably strong connection between AML and nuclear transport, leading to the hypothesis that deficiencies in nuclear transport may play an important role in leukaemia. In the proposed research we aim to collect convincing molecular evidence to confirm this hypothesis. When successful, this will not only trigger a new research direction, it will also open up an entirely new angle in the development of therapeutic strategies for AML.

Smart design of fungal cell factories for sustainable production of precursors for antitumor molecules.
Dr. M. (Mao) Peng (Westerdijk Fungal Biodiversity Institute, the Royal Netherlands Academy of Arts and Sciences)
Microbial cell factories to produce high-value chemicals from renewable biomass are attracting increasing interest, because they hold great potential for transforming current fossil-resource-based processes into a sustainable bioeconomy. We recently obtained the first experimental evidence of fungal synthesis of D-lyxose by Aspergillus niger, a high value rare sugar widely used as precursor for antitumor drugs. In this project I aim to identify and characterize the key genes related to fungal biosynthesis of D-lyxose, and based on this use metabolic engineering of A. niger to generate an efficient cell factory that utilizes cheap agriculture wastes for sustainable production of D-lyxose.

Reducing immunogenicity through bioengineering of human donor heart valves.
Dr. M.C. (Marijn) Peters (Eindhoven University of Technology)
Children with heart valve disorders risk the development of heart failure and require valve replacement with a cryopreserved donor valve. However, these are avital and cannot grow. Living donor valves would offer excellent outlooks for growth but face immune rejection. Recently, we have pioneered a gene-editing system to hide donor valves from immune rejection. Here, we will validate by using advanced techniques to characterise bioengineered donor valves in the presence of immune cells to mimic implantation. When successful, this new technology will have large implications for modern transplant technology and may prevent the use of immunosuppressants/anticoagulants and extensive animal testing.

Drop-on-Demand Solution for Improved Tissue Engineering.
Dr. S.C.M (Sarah) Pragnere (Eindhoven University of Technology)
Tissue engineering combines biology and engineering to reproduce organs in vitro. Bioprinting of cells in hydrogels is one of the methods to produce these in vitro organs. While most methods aim to create homogeneous cell suspension, we believe that heterogeneous cell repartition can help us recreate some aspects at the micrometer scale that traditional methods cannot. This could be used to reproduce the specific micro-architecture of different organs. To achieve this goal, we want to use a drop-on-demand system to precisely position the cells in 3D. If it succeeds, it will pave the way for a new tissue engineering method.

Illuminating the future: developing optically transparent gas diffusion electrodes for light-driven CO2 reduction.
Dr. S. (Sonja) Pullen (University of Amsterdam)
Gas diffusion electrodes (GDEs) are an emerging technology in electrochemical conversion of CO2. Because GDEs are made from black carbon-materials, in such systems light cannot be used to drive reactions like CO2 conversion. Illuminating light-responsive electrodes significantly reduces operating potentials required in electrocatalysis, thus allowing more sustainable energy use. This XS project aims at the development and implementation of novel materials for optically transparent gas-diffusion electrodes, enabling the use of light. In combination with integrated catalysts, novel electrode materials will find application in photo-electrochemical cells for light-driven conversion of gaseous pollutants such as CO2.

BATtle of the sexes: utilizing brown adipose tissue sex dimorphism to identify novel targets against metabolic diseases.
Dr. A. (Alba) Sabaté Pérez (Erasmus Medical Center)
Brown adipose tissue expends energy to produce heat and maintain body temperature. Stimulation of brown adipose tissue is therefore considered a treatment option to battle obesity. Women more frequently have active brown adipose tissue than men. We will employ these sex differences to obtain a better understanding of the underlying mechanisms regulating brown adipose tissue activity using human induced pluripotent stem cells (iPSc). By comparing male and female iPSc-derived human brown adipocytes, we aim to identify secreted factors that enhance brown adipose mass and activity. These proteins are ideal targets to enhance energy expenditure and treat obesity and its comorbidities.

String Printing: a breakthrough for solar cell efficiency and structures for microelectronics.
Prof. Dr. R. (Rebecca) Saive (University of Twente)
Printing high aspect ratio (tall and thin) features for electronic devices is highly complex, but sorely needed to enable unique functionalities for sensors, communication devices, and energy generation. Currently for solar cells, flat (low aspect ratio) metallic wires are used on the front to extract electricity. However, these reflect a significant portion of incoming light and is the largest single source of decreased efficiency. “String printing” enables ideal contact geometries which nearly negate this loss of light. Through this single step, solar cell efficiency can increase by 4-10%, which drastically reduces costs, land use, material use, and enhances sustainability.

Continuously “milking” aquatic single-cell plants for functional food ingredients: MilCowLg.
Dr. K.S. (Katherine Jennifer) Salazar Alekseyeva (Wageningen University & Research)
Aquatic plants such as microalgae can convert carbon dioxide into functional food ingredients like proteins, 10 times more efficiently than terrestrial crops. This is done while requiring no arable land, pesticides, fertilizers, and even fresh water. Nonetheless, their growth and processing are complex, translating into more expensive products. To address these issues we will develop an innovative continuous extraction of active compounds from microalgal cells without killing them. This “milking” process will allow us to reuse these cells again and again, effectively simplifying the approach and making it economically competitive, bringing these technologies closer to a wide-scale application.

Innovating T cell diagnostics through protein engineering.
Dr. F.A. Scheeren (Leiden University Medical Centre)
T-cells are the guardians of our immune system, but identifying T-cells that specifically recognize and attack infected cells is a major challenge. Detecting the major subset helper T-cells is difficult due to production of a protein that specifically tags them, called MHC-II. MHC-II also binds weakly, making detection even more difficult. Here we propose to use genome-engineered high protein-producing cell-lines called hybridomas. We will also use state-of-the-art DNA-nanotechnology to cluster multiple MHC-II proteins, which will drastically increase their ability to bind to T cells and improve detection. Our cutting-edge approach promises to unlock new insights into T-cell biology and diagnosis.

Singling Out Extracellular Vesicle Subpopulations for Biomarker Discovery.
Dr. M.L. ( Maria Laura) Tognoli (University Medical Centre Utrecht)
Cancer cells converse with the surrounding non-cancer tissue through the exchange of small vesicles as carriers of information, a process that is important for tumour growth. These small carriers are invaluable tools for detection and monitoring of cancer progression, however, similar to cells in our body, they come in different types, each carrying a different function. We hypothesize that each set of vesicles affects specific non-cancer tissue surrounding the tumour and we propose a new approach to separate vesicle subsets and study their effect on non-cancer tissue. Ultimately, our findings will expand the opportunities for cancer prognosis and therapy.

Message in a package: characterizing amyotrophic lateral sclerosis through extracellular vesicles.
Dr. S. (Suzy) Varderidou-Minasian (University Medical Center Utrecht
Amyotrophic Lateral Sclerosis (ALS) is a neurological disease that affects the nerve cells that control voluntary muscle movement, like walking and talking. The cause of ALS is unknown and there is currently no cure. Recent studies provide evidence that cells release packages of vesicles loaded with molecules important in intercellular communication. I hypothesize that ALS cells release packages with ALS-associated molecules which are toxic to healthy cells. I will test this hypothesis by using human model systems to mimic ‘brain-disease-in-a-dish’ and uncover how these packages contribute to the disease. Here, I can characterize the start of ALS pathogenesis.

High resolution volumetric bioprinting of large tissue models.
Dr. A. (Alexis) Wolfel (University of Twente)
Laboratory-made tissues and organs are re-shaping medicine: they are useful to understand diseases; can reduce the use experimental animals; and may facilitate scalable organ transplantations. However, while natural tissues possess intricate architectures throughout their entire bulk, current methods to produce engineered living tissues only allow for either large volumes at low resolution or high resolutions within small tissue volumes. This limitation hinders the use of engineered tissues. We propose to develop a beyond-state-of-the-art 3D-printing technology to bioprint tissues with unprecedented speed and resolution. This novel technology will thus uniquely offer ability to rapidly produce large tissues at high resolutions.

Can AI learn the laws of physics and chemistry in protein folding?
Dr. L. (Li) Xue (Radboud universitair medisch centrum)
Self-supervised learning (SSL) algorithms, like chatGPT, can learn the grammar of natural languages without giving specific instructions. We will develop 3D-GPT, an SSL algorithm that learns the physical and chemical rules of protein folding from the analysis of three-dimensional (3D) protein structures. Specifically, we will explore the capability of 3D-GPT to model the energy for protein folding and use it to fold small therapeutic proteins. Like other SSL algorithms, once pretrained, 3D-GPT can be fine-tuned to solve a wide range of applications, for example, identifying disease-causing mutations, and aiding cancer vaccine design.

Copper-Catechol Synergy for the Development of an Energy-Dense and Long-Lived Redox Flow Battery.
Dr. E. W. (Evan Wenbo) Zhao (Radboud University)
The transition to a greener and sustainable future requires efficient and affordable technologies for large scale energy storage. Current technologies are mainly based on lithium-ion batteries, but the high maintenance, safety issues and limited availability forms a challenge in the current industry. Copper redox flow batteries are a promising alternative for large scale renewable energy storage, because copper is an earth abundant metal. Our goal is to develop a new generation of copper redox flow battery that have a long lifetime (>20 years) and higher energy density than the state-of-the-art copper redox flow batteries.