Projects that promote the 3Rs

Prostate and breast cancer are among the top five most prevalent types of cancer and are responsible for 70% of all skeletal metastasis. While metastasized there are shortage of efficient pharmaceuticals. Due to lack of models accurately mimic a drug’s mechanism of action in the human body it is a hurdle for drug development. This leads to numerous unnecessary uses of animals that need to be addressed for a 3Rs perspective.

The overall purpose of this project is to develop a high-throughput in vitro platform for the discovery of novel pharmaceuticals for bone metastasis mimicking the mechanism of action in the human body that drive cancer metastasis.

The project includes a cross-disciplinary team with experience in developing drug discovery platforms. The researchers will include both bone- and cancer cells since their communications has a crucial part while cancer is spread out in the body. The cells are cultured on a matrix while exposed to mechanical loading that appears during the metastatic process. Anna Fahlgren and her group have previous demonstrated that mechanical loading induces a specific release of soluble factors that affect their response on common anti-cancer pharmaceuticals.

Getting 3Rs funding from the Swedish Research Council is important, according to Anna; to get acknowledge for her research, both in basic science but also in a 3Rs perspective. Anna and her colleagues will include knowledge from both academia and industry during the project. A model that reduces and replaces research animals is important for both academic lab and industry in regards for ethical and economical sustainability.

More and more children are receiving diagnoses that can be related to disorders in brain development, which can be linked to chemicals in our environment. Anna Forsby's research group wants to develop a strategy to be able to assess the risks of being exposed to chemicals during pregnancy by combining information produced and calculated in cell and computer models.

There are many scientific publications and large data sets regarding how chemicals affect nerve cells in cultures. Most often, there is no systematic evaluation of all published data in terms of causality or different effects at different exposure conditions. One aim of this project is to establish connections between these terms from the time a substance interacts with a biological molecule, subsequent effects in the cells and the brain and a link to diagnoses.

In order to use data determined using cell models for risk assessments, one must translate concentrations that cause damage to cells similar to fetal neurons to the dose the mother needs to be exposed to cause these damages. The second aim of the project is to make these estimations by using computer models that include information about the chemicals' absorption, distribution, breakdown and excretion in the body.

The 3Rs grant from the Swedish Research Council enables the development of a strategy that includes relevant cell models and advanced computer models in order to develop faster, cheaper and safer tests with fewer animals that do not need to be exposed to high doses.

Globally, millions of fishes are used in laboratories and they are the second most popular experimental model used in experiments in the EU, with approximately 60 000 used in Sweden annually.

While most fish undergo anaesthesia during procedures that include surgery, analgesia, or pain-relief, is not routinely provided. This project aims to address a key question to improve the welfare of animals in research: how can we refine invasive experiments using fish by employing pain-relief?

The project will investigate the impact of a range of pain-relieving drugs on both young and adult fish to identify which drugs at what doses are effective in reducing pain. A serious concern that researchers have relates to the possibility that these drugs may affect their data so Lynne Sneddon and her colleagues will explore a range of scientific measures to assess any confounding effects.

Further they will explore the pharmacology of effective drugs to determine when to readminister. These results can be used to guide scientifically informed and humane choice of pain-relief as well as developing pain management protocols in fishes.

This project is according to Lynne, a crucial step in refining experiments using fish in laboratories across the globe; improving experimental fish welfare as well as potentially reducing the severity of a large number of experiments.

Glioblastoma Multiforme (GBM) is the most common form of malignant brain tumour. Death rates from cancer have generally decreased in recent decades thanks to improved treatments, but unfortunately this is not the case for GBM. Part of this is because current ways of testing new treatments are not good enough. Although traditional cell cultures and animal models are used on a large scale, they are not sufficiently close to the architecture and complexity of the GBM tumour. New models that better reflect the characteristics of the tumour are needed and they must be evaluated through careful comparisons with the tumour disease for which they are intended to be a model.

Mats Nilsson’s research group has developed a technique called in situ sequencing. It is about being able to look at gene expression in individual cells in intact tissue sections. This makes it possible to see exactly which cells build up the tumour and contribute to its growth.

Mats and his colleagues are currently studying GBM tumours from patients to determine their characteristics. To do so, they will create organoids – a kind of human mini-organ. The organoids contain a normal human brain component from induced pluripotent stem cell lines, so-called iPSC cells, as well as growing tumours derived from tumour cells in patients. The researchers will characterize them in exactly the same way as they characterize the patients' tumours, in order to assess the relevance of the organoids as a model.

The ultimate goal is to establish a human in vitro and in silico model for drug development targeting GBM tumours. Such a model will not only be able to replace the animal models used today, but also has the potential to be both better and less expensive. Mats hopes that this will speed up the development of effective drugs against the deadly disease.