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Innovation examples
HealthToxicologyIn vitro
Thyroid Hormone & Brain Development: animal-free models for human safety assessment
The environment can have a significant impact on a child's health even before birth. Brain development begins in the first trimester and continues until the age of 25, with thyroid hormone playing a critical role. During early pregnancy, the fetus depends on the mother's thyroid hormone, and a disruption in the thyroid hormone balance can lead to cognitive and motor impairments in the child. As part of the VHP4Safety project, we are developing in vitro tests to measure the developmental neurotoxic effects caused by disturbances thyroid hormone concentrations. Current testing guidelines do not always include testing for neurodevelopmental effects, highlighting the need for new non-animal methods. At the Erasmus Medical Center, human cell lines representing brain cell types are cultured to study the effect of chemicals on the thyroid hormone balance. RIVM uses human stem cells to create neuron-astrocyte networks that mimic brain development. By combining these different assays and models, we are creating a comprehensive human-based testing strategy to assess developmental neurotoxicity. These advances are a critical step toward eliminating animal testing while protecting the health and environment of future generations.
Innovation examples
HealthToxicology
Zebrafish in toxicity testing
Zebrafish are increasingly recognised as a useful model for toxicity testing of chemical substances. Testing strategies are becoming more based on mechanisms of toxicity structured in adverse outcome pathways describing the chain of events leading to toxicity or disease. Using a battery of dedicated in vitro and in silico assays, insight can be gained in how exposure leads to disease. For certain diseases it is known that toxicity relies on the interaction between different organs and cell types, which requires research on whole organisms in addition to simple in vitro models. The zebrafish is considered a valuable whole organism model in a mechanism-based testing strategy. At RIVM, the zebrafish embryo model is used for testing the effect of chemical substances on several adverse outcomes and diseases.
For more information see: https://ehp.niehs.nih.gov/doi/10.1289/EHP9888; https://doi.org/10.3390/ijerph18136717; www.linkedin.com/in/harm-heusinkveld
Innovation examples
In vitroOrgan-on-Chip
Unified organoid system for modeling heart and kidney interaction on-a-chip
Beatrice Gabbin is a PhD candidate at the Anatomy and Embryology Department of the Leiden University Medical Center. Her project is shared with the Nephrology Department and focusses on the study of the cardiorenal axis in vitro. Both heart and kidneys have vital functions in the human body and reciprocally influence each other’s behavior: pathological changes in one can damage the other. There are already multiple independent in vitro (human) models of heart and kidney, but none have so far captured their dynamic crosstalk. The aim of the project is therefore to develop a microfluidic system which can be used to study heart and kidney interaction in vitro. For this purpose, cardiac microtissues and kidney organoids derived from human induced pluripotent stem cells are generated and loaded onto a 3D perfusion chip for their dynamic co-culture. This system enables the study the cardiac and kidney interaction with a high level of control. The validation of a unified organoid system will enable the investigation of diseases involving the two organs and their potential treatments. Read more via the link in the video and https://doi.org/10.1016/j.mtbio.2023.100818.
Expert interviews
Toxicology
How do we use human data in risk assessment
In this video, EFSA explains how they do risk assessment and what the role of NAMs can be in this process.
Innovation examples
HealthInnovationIn silico
Using data and computational modelling in biomedical research
Bioinformatics and systems biology hold great promise to translate the wealth of biological data into meaningful knowledge about human health and disease. The group of Bas Teusink helps biologists to deal with high throughput data, for example metabolomics (how cell metabolism works) and proteomics (how protein networks work) from patient material or cell cultures. This can help to better understand disease mechanisms and aid drug targeting or personalised medicine. In the future, combining data from different models (in vitro, in vivo and human data) could become a digital model of humans, or a “ digital twin”.
Click on the link in the video to watch more or read the interview with Bas (and Jaap Heringa) he[https://vu.nl/en/research/more-about/using-data-and-computational-modelling-in-biomedical-research]re.
Innovation examples
HealthIn vitroOrgan-on-Chip
An iPSC-derived blood-brain barrier to model neurodegeneration
The blood-brain barrier is a layer of cells that protects our brain from harmful compounds. However, due to this tight barrier, many drugs to treat neurological diseases cannot enter the brain either.
There are currently no good models to test these types of drugs. Henrique Nogueira Pinto is a PhD candidate at the Vrije Universiteit in Amsterdam. He is developing a blood-brain barrier model coupled to mini-brains. With this model, he aims to more reliably test how drugs can be transported over the blood-brain barrier and what their effect on the brain is.
Click on the info button for the full version of the video. Click here (https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-022-00316-0#Sec3) for a review of the current status of in vitro models for the blood-brain barrier.
Projects and initiatives
HealthToxicology
The NAM Navigator: A unique repository for information on the validation and acceptance of New Approach Methodologies
The NAM navigator is an innovative knowledge portal to navigate you to and through valuable information on the development, standardization, validation and acceptance of New Approach Methodologies (NAM). The NAM Navigator acts as an online guide that provides specific information needed in each of these steps, thereby increasing the broad use of animal-free innovations. Follow the link in the video to start navigating!
Innovation examples
ToxicologyInnovationIn vitro
Human neuronal cell models for in vitro neurotoxicity screening and seizure liability assessment
Anke Tukker was a PhD candidate in the Neurotoxicology Research group of Dr. Remco Westerink at the Institute for Risk Assessment Sciences at Utrecht University. Dr Westerink’s research group investigates the mechanisms of action of toxic substances on a cellular and molecular level using in vitro systems. Anke's project aimed to develop a human induced pluripotent stem cell (hiPSC)-derived neuronal model for in vitro neurotoxicity screening and seizure liability assessment. Using micro-electrode arrays (MEAs), she showed that these models mimic in vivo neuronal network activity. When these hiPSC-derived neurons are mixed with hiPSC-derived astrocytes, they can be used for in vitro seizure liability assessment. Comparing these data with data obtained from the current used model of ex vivo rodent cortical cultures, she found that these human cells outperform the rodent model. Here research thus contributes towards animal-free neurotoxicity testing.
Anke Tukker has won the public vote of the Hugo van Poelgeest prize 2020 for her research on human neuronal cell models for in vitro neurotoxicity screening and seizure liability assessment.
Neurotoxicology Research Group, IRAS, Utrecht University: https://ntx.iras.uu.nl/NTXatIras
Innovation examples
ToxicologyIn vitroOrgan-on-Chip
Cartilage-on-a-chip for studying joint degenerative diseases
Carlo Alberto Paggi is currently a PhD candidate at the University of Twente in the research group of Prof. Marcel Karperien and Prof. Séverine Le Gac. Karperien’s lab focus on the biological aspects of osteoarthritic research while Le Gac’s specialize in organ-on-chip development. The project of Carlo Alberto is developing a joint-on-chip platform to create a reliable in vitro model to study disease progression in osteo- or rheumatoid arthritis. The model combines different organ-on-chips aimed at replicating each a tissue around the joint such as cartilage, bone and ligaments. This new technology focuses on better reproducing human models and at substituting the use of animal models for drug research. If you want to know something more about the project and the groups, you can follow the link in the video.
Carlo Paggi was nominated for the Hugo van Poelgeest prize for his research on a cartilage-on-a-chip model to study joint degenerative diseases
Karperien’s lab of Developmental Bioengineering: https://www.utwente.nl/en/tnw/dbe/
Le Gac’s lab of Applied Microfluidics for BioEngineering Research: http://www.severinelegac.com/
Linkedin: https://www.linkedin.com/in/carlo-alberto-paggi-76500b135/
Innovation examples
HealthToxicology
New approaches for cancer hazard assessment
Chemical substances are subjected to assessment of genotoxic and carcinogenic effects before being marketed to protect man and the environment from health risks. For cancer hazard assessment, the long-term rodent carcinogenicity study is the current mainstay for the detection of nongenotoxic carcinogens. However, carcinogenicity studies are shown to have prominent weaknesses and are subject to ethical and scientific debate. A transition toward a mechanism-based weight of evidence approach is considered a requirement to enhance the prediction of carcinogenic potential for chemicals. At RIVM, we are working on this alternative approach for cancer hazard assessment, which makes optimal use of innovative (computational) tools and be less animal demanding.
For more information, click on the link in the video or read on here (https://doi.org/10.1080/10408444.2020.1841732) and here (https://doi.org/10.1080/10408444.2018.1458818).
Contact the expert (https://nl.linkedin.com/in/mirjamluijten)
Innovation examples
ToxicologyIn vitro
Stem cell differentiation assays for animal-free developmental neurotoxicity assessment
Victoria de Leeuw was a PhD candidate in the research group of prof. dr. Aldert Piersma at the RIVM and Institute for Risk Assessment Sciences at Utrecht University. Piersma's lab studies the effects of compounds on development of the embryo during pregnancy with, among other techniques, stem cell cultures. The project of Victoria was aimed to differentiate embryonic stem cells of mouse and human origin into neuronal and glial cells, which could mimic parts of differentiation as seen during embryonic brain development. These models were able to show some of the known toxic mechanisms induced by these compounds, congruent with what they we hypothesised to mimic. This provides mechanistic information into how chemical compounds can be toxic to brain development. Therefore, these two stem cell assays make a useful contribution to the animal-free assessment of developmental neurotoxicity potential of compounds.
Victoria is nominated for the Hugo van Poelgeest prize 2022 for excellent research to replace animal testing.
Questions
HelpathonsHealth
Helpathon #11 – Can you help Francesca?
Francesca Stillitano (UMC Utrecht) is a geneticist and an Assistant Professor at the Department of Cardiology. Francesca is currently working with mice models and with human tissue-based in vitro models to develop and test new gene therapies for a rare cardiomyopathy. Can you help Francesca with developing gene therapies for curing inherited cardiomyopathies without the use of animal models? More information can be found here (https://www.helpathonhotel.org/coming-up).