Discussion on the BBSRC Survey report on the use of models in research

Context 

The term ‘research models’ encompasses a breadth of possible approaches used in both fundamental research and drug development from in silico computational models to whole organisms. The BBSRC, in consultation with the Physiological Society, undertook a survey of scientists to understand the current status of the use of research models with the aim to understand how best this discipline can be maintained and strengthened. A wide range of research models were included in the survey but with the majority of responders being researchers using whole organisms.  

Summary of key findings and recommendations 

Based on the data generated, research models involving whole organisms remain a critical part of research methodology. The rationale for the choice of model were mainly their physiological relevance and availability of genetic tools, which were seen as key to providing the best model for the research question. It was also evident that the availability of expertise was also an important factor influencing the choice of model being used. Whilst 15% of those who responded used only a single model, most (83%) used multiple models and integrated whole organism work with cell culture and tissue-based methods which facilitated research into different aspects of the research question. A perhaps surprising finding was that 50% of models had been used for more than 10 years and those who were looking to change model were more likely to be from a non-academic organisation. 

When considering the future, whole organisms remained the most popular choice although 2D and 3D cell culture, organoids and computational/in silico models were all predicted to increase in use. Although most respondents were confident in their choice of model, changes in regulations and a lack of funding were seen as impeding innovations within their research. There was particular reference to regulatory bodies and whole organism usage making the UK less competitive due to higher costs and administrative burden. The main challenges and barriers to future model choice were seen as training and expertise including regulatory knowledge. Additional factors include a lack of validated novel models or investment to develop these or enable researchers to switch models. Lack of availability of genomic information and costs of generating and validating new models were also identified as barriers.  
The working group focused on two aspects of this survey in their discussions and subsequent recommendations: 

  1. Choice of model 
  2. Animal research 

In relation to the choice of model, there was some apparent reluctance in academia to change models which seems mainly to link to a perception that this is difficult and costly. There was also a perception that changing model might risk failure and negatively impact funding. The complex nature of many models and levels of skill needed to generate and work with specialist models is also a challenge and may prevent researchers from using the ‘best’ model for their question or from piloting a novel model.  

The working group recognised the challenges researchers face and identified a number of recommendations which would support the use of research models in the future. These included: 

  • Ensuring that peer review panels and committees have appropriate expertise to assess projects using either traditional models or those seeking to innovate new approaches. Panels should also recognise the time and cost implications of changing models, but that this is critical to future developments.  
  • Seeking to develop a cross-disciplinary and multisectoral engagement routes across both animal and non-animal technologies and work across funders and professional societies to improve sharing of expertise. 
  • Recognising the importance of whole animal studies, particularly the need to invest in large animal facilities in the UK, but to also identify opportunities to accelerate the development of non-animal technologies. 
  • Working with other funders to support model development and validation studies and to consider how comparative biology might contribute to future model development. 

Relevance to pharmacology 

Research models have played a crucial role in pharmacology research and the development of safe and effective treatments. Where early drug development was heavily reliant on whole animal-based methods for screening novel compounds through to efficacy and safety testing, much of the screening is now done using non-animal methods. This has enabled much larger compound libraries to be evaluated and reduced the relative numbers of animals being used in drug development. These types of assays have also become important in academia where they provide researchers with methods to investigate the molecular basis of drug-receptor interactions and the complexities of receptor dynamics in downstream signalling. However, these have their limitations when answering questions about both health and disease which represent complex states within the human body. As our understanding of human biology develops, we are increasingly aware of the complex interactions between body systems as well as how they are influenced by environmental factors. This complexity necessitates studies in whole organisms which are complimented by non-animal models but as yet cannot be fully replaced.  

In many areas of pharmacology, research models have developed but in quite selective ways with most focus on the generation of genetically altered animals. There has been surprisingly little development in other aspects of modelling human disease and many of the disease models used in both fundamental research and drug development have changed little in the last few decades. In my own field of psychopharmacology, a huge number of new genetic models have emerged, many of which carry mutations to genes identified as risk factors from population genetics. However, very little progress has been made in terms of the methods used to quantify the animals arising phenotype, with most research still using methods development as pharmacological models to predict drugs acting through specific receptor targets i.e. predictive but not construct or translational validity*. This is a major limitation when trying to study mechanisms and identify novel treatment targets and has also seen a very large number of drug candidates fail to translate to the clinic. However, the costs of validating new research models are huge and our own experience in developing a translational method for depression research illustrates this. Our work developing the affective bias test has taken more than 5 years to achieve initial validation and has only been possible with support from industry. In my experience, funders remain cautious about supporting novel models even with pilot data and, whilst happy to criticise established models, there is still a lack of recognition and support for this important area of research. Hopefully this BBSRC report will see this change and with greater emphasis on investment in model development, dissemination and training. 

*

Predictive – The model responds to treatments in a way that predicts the effects of those treatments in humans 

Construct - The model recreates the aetiological processes that cause a human disease, and thus replicates neural and behavioural features of the illness 

Translational - The characteristics of the model reflect the human condition and the findings from animals translate to those in the clinic e.g. similarity with symptoms, efficacy of treatments and time course 
 

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Published: 25 Aug 2022

About the author

Professor Emma Robinson


 

Emma completed her BSc(Hons) and PhD in Pharmacology in Bristol. She was awarded an RCUK Academic Fellowship with the BPS and is now based in Bristol’s School of Physiology, Pharmacology and Neuroscience. The groups primary focus is psychopharmacology research including the development of new animal models which is complemented by studies relating to the welfare of laboratory animals. 

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