Sabine Hölter, Coordinator of the European Brain Research Regional Cluster PREMOS, draws attention to the translational value of animal models in brain research
More than one in two Europeans now has a brain disorder, causing enormous social and financial costs that require effective investment in brain research in Europe. This should include the use of animal models to better understand disease etiology and develop strategies for prevention and treatment.
For 20 years, the European Brain Council (EBC) has been working to advance brain research with the ultimate goal of improving the lives of Europeans with brain diseases. To streamline and better coordinate brain research across Europe while facilitating global initiatives, the EBC will support the Human Brain Project, now transitioning to EBRAINS, the EU Joint Program on Neurodegenerative Diseases, and EU funding. We have compiled ERA-Net NEURON under the Contribution Project. European Brain Research Area (EBRA).
To facilitate collaboration and exchange in all areas of brain research, EBRA launched six ‘clusters’ (1), including the Predictive Model System or PREMOS cluster. Our ambition is to build a broad coalition to ensure the translational value of animal models in brain research that cannot be replaced by alternative methods.
we need to join forces
The use of animals for scientific purposes has long been practiced in brain research.Today, many brain research problems can be studied using alternative methods that address the micro-level of the brain (i.e., cells and synapses), cell-based or
Organoids cannot model the complex behavior and complex physiology of organisms. At the macro level, brain research still requires in-vivo studies in animal models required for therapeutic development/survey.
But how can we be sure that the model being used is correct?
The major gaps hindering the transition from laboratory research to the clinic are:
(i) the majority of psychiatric and neurodegenerative disorders are complex and of unknown origin;
(ii) clinical diagnosis is not usually based on neurobiology;
Human clinical findings for use in preclinical studies.
(iii) the models used are often poorly described and validated;
The PREMOS cluster has developed some ideas to address these gaps.
To better understand the origins of encephalopathy, there is a need to improve translation of human clinical findings for use in larger preclinical studies and to better involve patients in preclinical discussions. I have.
Agree what the priority is. To optimize this transfer, it should be imperative that human studies provide quantitative and biological data.
Genetic and environmental contributions to the etiology of brain diseases
There is also a need to better understand the genetic and environmental contributions to the pathogenesis of brain diseases and to better understand early life, including adolescence, from both a biological neurodevelopmental and clinical perspective. This expands the range of preventative measures against brain health problems in adulthood.
One way to leverage existing resources and prevent unnecessary duplication (and use of animals) is to enhance access to existing animal models and their detailed information. For example, national European and global repositories, including negative results available in IMPC models.Genetic and phenotypic cross-species comparisons of such comprehensive datasets, for example, will help us better understand the pathogenesis of neurodevelopmental disorders.
Comorbidities that interfere with quality of life and life expectancy. Attempting to understand the common genetic underpinnings of such comorbidities in appropriate animal models could have major implications with respect to diagnosis, early detection of disease, and patient management and treatment.
Interspecies comparisons should be made more extensively
To ensure that fundamental neuroscience discoveries in animal models are translationally relevant, the biological mechanisms and functions studied in the model should resemble those in humans. Therefore, more extensive cross-species comparisons, including similarities in brain function, symptoms, target and drug responses, need to be conducted to validate the model. Animal models are often confined to controlled environments and specific genetic backgrounds, and thus display only a subset of the functions observed in humans. Additional experiments or different study designs are required to overcome these limitations.
Preclinical evidence to justify clinical trials should be based on the stepwise use of multiple models from different species to increase the predictive value of preclinical evidence for translational success. For preclinical evaluation of therapeutic efficacy, multiple doses over longer periods should ideally be investigated. Authors, reviewers, and editors should make clear statements about study limitations and scope of conclusions, and the use of formal nomenclature and detailed model descriptions.
Training, quality control, and quality control need to be improved to improve the quality of preclinical data. Reproducibility can also be improved by further automating the evaluation. This is to reduce variability and allow e.g. to provide long-term data on the efficacy of therapeutic interventions. This will allow the development of translational digital biomarkers and early intervention points.
Investigators with diverse expertise in basic and clinical neuroscience, animal and human genetics, bioinformatics, data science, etc. need to work together, and there is more interaction between preclinical scientists, clinicians and patients. Close interactions should be facilitated to ensure the translational value of animal models in brain research. Join forces across disciplines for the benefit of patients and to further reduce the number of animals needed!
(1) A cluster is understood as an association of research projects that can be directed towards basic research, clinical research, and/or methodological approaches under a common topic and disease area.