Two Dutch research groups and industry will jointly develop animal-free innovations via the ZonMw call Create2Solve. Over the next five years, the projects will focus on a 3D model of human brain cells and a better test method for potentially toxic substances. The projects will contribute to limiting the use of laboratory animals in both industry and science.

The selected projects: a better test method for potentially toxic substances
 

One of the provisionally awarded projects is from Dr Nynke Kramer (Utrecht University, Institute for Risk Assessment Sciences), in collaboration with the National Institute for Public Health and the Environment (RIVM) and the private partners Vivaltes and Toxys. This project focuses on developing a robust animal-free test method to establish the toxic dose of poorly soluble substances. ‘If the reliability of animal-free test methods is increased, users will gain more confidence in these and use them as an alternative for animal experiments,’ says Kramer.

The project will provide a solution for Challenge 1: the problem that was previously defined by a consortium consisting of Shell, Sabic and LyondellBasell. As a result, the questions have been posed by the end-users. ‘The outcomes of the project are therefore also something that the end-users will genuinely benefit from’, says Kramer. ‘This approach could enable us to realise an animal-free era in toxicology sooner.’ The project will also considerably limit the number of animal experiments by focussing on more than just the science. James Wheeler, Senior Eco-Toxicologist at Shell, says: ‘Bringing together several parties creates an ideal situation for the successful implementation of animal-free innovations in practice, also at the international policy level.’

A 3D model of human brain cells


The second project provisionally awarded funding is from Dr Femke de Vrij (Erasmus MC) in collaboration with the private partner Core Life Analytics. It focuses on developing an animal-free 3D model with human brain cells that will contribute to drug development and research. ‘Especially for complex brain diseases that are difficult to investigate in laboratory animal models, it is vitally important to do research with human material’, says De Vrij.

Therefore, this project will provide a solution for Challenge 2, the problem defined by the consortium consisting of Charles River Laboratories and Danone Nutricia Research. The design of the project is regarded as promising for medical applications. By combining in-depth academic knowledge with the input of the application-oriented industry, models will be created that could be used for the successful development of new drugs. The collaboration with industry opens new doors as well. ‘The scaling up of experiments and large-scale data analysis are now possible, whereas usually, an academic research group does not have the capacity for this’, says de Vrij.

Create2Solve


With the call Create2Solve, which is part of the programme “More Knowledge with Fewer Animals”, ZonMw and industry together undertake demand-driven research into animal-free innovations. With this, ZonMw supports the development of animal-free innovations with an impact that aim to provide marketable methods, models and/or services. The funding for Create2Solve has been made available by the Ministry of Agriculture, Nature and Food Quality (LNV), the Dutch Research Council (NWO) and the Dutch Society for the Replacement of Animal Testing.

In July 2019, phase 0 of Create2Solve was completed. In this phase, two questions, so-called Challenges, from two consortia of companies were articulated in a call for proposals. For these Challenges, knowledge institutions could submit a project proposal in collaboration with a private partner. Three “proof-of-concept” projects were admitted to phase 1 in December 2019. Two of these projects, one per challenge in the current phase 2, have been selected to develop their proposals into an animal-free innovation, together with the private parties involved. Each of the project groups will receive one million euros and will be given a maximum of five years to realise the project.

Summaries of the projects

Project Challenge 1: Better in vitro Dosing (BID): Framework and technology development for improving the quality of in vitro data - Dr Nynke Kramer (Utrecht University, Institute for Risk Assessment Sciences)

(Private) partners: Vivaltes, Toxys and RIVM
Challenge holders: Shell, Sabic and LyondellBasell

To reduce animal experiments, in vitro cell systems will be used to establish the toxic dose for a test substance. Generally, the nominal concentration (the amount of substance added divided by the volume of medium) is used to establish concentration-effect relationships. However, in humans and animals, that leads to poor predictions of the toxic dose of volatile, lipophilic and unstable substances because only a small fraction of these substances ends up in the cells. In this project, we will keep the evaporation, breakdown and bonding of these substances to plastic and plasma proteins in vitro under control by using small, closed glass pots and well collection plates that are dosed using a polymer (so-called partition-controlled dosing). We have developed a decision tree that clarifies under which conditions it is recommended to use these techniques.

Project Challenge 2: 3D MICro-brains: An animal-free human 3D cortical network platform for screening myelination and inflammation phenotypes. 3D Myelination & Inflammation Cortical network platform (3D MICro-brains) - Dr Femke de Vrij (Erasmus MC)

Private partner: Core Life Analytics
Challenge holders: Charles River and Danone Nutricia Research

Recent developments in induced pluripotent stem cell (iPSC) technology make it possible to implement
cell-type-specific human cell culture models for research and drug development. In this project, researchers will develop a 3D model with human brain cells that can simulate the brain’s complex structure in early development. These micro-brains (3D MICro-brains) will reduce the modelling of the frontal cortex to its essence in a format of, literally, a millionth of the normal brain volume. The platform contains all relevant brain cell types: functional neurons and glia in layered radial structures, including astrocytes, myelin-producing oligodendrocytes and microglia that play a crucial role in inflammatory processes in the brain. Furthermore, this model is entirely animal-free and thus contributes to the transition to animal-free research. Due to its scale and reproducibility, this platform is ideally suited for automated applications in drug development and research, which will be further elaborated with a company that will add automated, high-resolution image processing to this project.

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