The problems with studying psychiatric disorders
Understanding the causes of mental health conditions, and understanding how to remedy them, is a difficult business. This is for two major reasons: firstly, there is considerable variability within patients with regard to their symptoms, their lifestyles, their medication regimes, and their social circumstances – hence, establishing definitive cause and effect relationships is challenging and requires the study of large and well-characterised participant cohorts. Secondly, whilst improved imaging techniques allow the gross structure and function of the brain to be assessed in vivo, the organ cannot be biopsied for detailed analysis; samples of brain tissue that can be obtained are often affected by post mortem perseveration processes and/or by factors including drug treatment, trauma, infectious disease or seizures.
These combined challenges explain why effective new drugs for treating psychiatric disorders have not been forthcoming, and why we continue to rely on medications which often have limited efficacy or undesirable side-effects.
Benefits of using animal models
The challenges inherent in human research can be addressed to some extent by studies in animal models. Historically, a wide range of animals have been used to provide insights into developmental, psychiatric and degenerative conditions ranging from invertebrates such as worms and fruit flies and vertebrates such as zebrafish and monkeys. In Cardiff, and elsewhere, rodents (mice and rats) are the ideal species for mental health research; being mammals, these creatures have similar physiology to humans, allowing for optimal cross-species translation of findings.
Animal models provide a degree of experimental control that cannot be achieved in human work i.e. we can systematically vary one parameter (such as an animal’s genetic make-up, or its environment) and examine resultant effects on brain and behaviour in a standardised manner. In particular, we can undertake experimental manipulations that could not be ethically or practically undertaken in humans e.g. administering drugs, lesioning parts of the brain, introducing genetic manipulations, or altering the in utero environment. We can examine brain tissue from such models in intimate detail, an important advantage given the cellular complexity of this organ.
Psychiatric disorders are defined on the basis of abnormal behaviour. Whilst research techniques such as cell culture and computer-modelling can provide insights into fundamental cellular and brain network processes, it is only through ‘whole organism’ research that we may understand the complex ways in which the brain and the body interact to give rise to a behavioural output. The importance of interactions between the brain and the rest of the body has recently been highlighted by evidence from Cardiff University and elsewhere; specifically, the immune system which regulates the body’s defence against infection, appears to play a key role in vulnerability to a wide variety of ‘brain’ disorders including depression, schizophrenia and Alzheimer’s Disease.
Through studying animal models, we can identify aberrant brain and body processes that can give rise to behavioural and neurological symptoms, and that may be amenable to modulation; these models may subsequently be used to screen for, and test the efficacy of, new pharmacological or behavioural treatments for use in the clinic. Importantly, this basic research should also allow us to understand and treat pathology in animals (e.g. perseveration in zoo animals or epilepsy in some dog species) much more effectively.
All of our research is approved and closely monitored by the Home Office, and abides by the principles of the 3R’s i.e. using alternatives wherever possible (‘replacement’), using the minimum number of animals to achieve a robust result (‘reduction’) and improving testing procedures such that they minimise the adverse effects on the animal (‘refinement’).
Limitations of animal models
Understandably, there is opposition to using animals in research, particularly where we are inducing analogues of distressing mental disorders. It is important to recognise that we only use animals when no other method of investigation would suffice and where the likely benefits significantly outweigh the costs in terms of animal welfare.
It is important to appreciate that no one animal model can completely recapitulate all of the features of a complex psychiatric disorder, it is difficult to assess intention in animals, and animal models may be of limited value in helping to understand human-specific phenomena such as brain asymmetry, language or psychosis. Moreover, human biology is unique and often unpredictable; hence, findings from animal models should be extrapolated with a degree of caution and should never be expected to completely explain the human condition or to predict the efficacy of new therapeutic approaches. To maximise the chances of cross-species translatability, animal models should be chosen and specified stringently.
Animal Welfare is paramount
The welfare of animals used in our research is paramount, and we have many safeguards in place. We strive to refine procedures so the degree of suffering for animals is kept to the absolute minimum. The animals are maintained at the highest standards and our highly-trained animal technicians keep up to date with the utmost levels of animal care, through on-going professional development from the Institute of Animal Technology.
All of our research involving animals is aimed at the alleviation of human and veterinary disease through the advancement of medical, dental, biological and veterinary understanding and all projects undergo stringent ethical scrutiny.
All research at Cardiff University adheres to the Animal (Scientific Procedures) Act 1986, which states that animals may not be used if there is a scientifically satisfactory alternative method or testing strategy not entailing the use of a protected animal. Hence, animals are used only when there is no alternative.
In May 2014 we signed the Concordat on Openness on Animal Research in the UK. You can find a breakdown of the type of animals used within Cardiff University on our website. This information is published annually and supports our commitment to be transparent and open about the work we do involving animals. We agreed to be clear about when, how and why we use animals in research and aim to enhance our communications with the media and the public about our research using animals. As part of this commitment we provide lay summaries of research that involves animals for all new granted project licenses.
We also work closely with organisations such as Understanding Animal Research to educate the public about why, and how, we undertake animal research.
However, the study of animals remains essential. Animals provide the only way for us to develop our scientific knowledge and produce treatments and cures for many serious conditions. Research using animals has saved and improved the lives of millions of people and animals.
Without research involving animals we would have no modern anaesthetics, hip replacements or life support for premature babies. There would be no heart or kidney transplants, no kidney dialysis or heart pacemakers, no treatment for diabetes, no vaccines for polio, diphtheria or malaria – or for a number of animal diseases.
Animal research in Cardiff
We are currently undertaking a large Wellcome Trust-funded project to investigate how genetic mutations associated with psychiatric illness in humans affect brain function and behaviour . This project brings together clinicians and basic scientists, and uses complementary approaches in psychiatric genetics and contemporary neuroscience (including sophisticated modelling in animal (rat) and cellular systems) in an effort to provide novel and important insights into the biology underlying psychiatric and neurodegenerative disorders.
Cardiff University has made considerable progress of using animal models to provide insights into the neural and psychological mechanisms underlying aspects of healthy and abnormal behaviour. Recent notable successes in this area include: evidence for the idea that impaired nutrient provision during fetal life may result in later behavioural abnormalities, insights into memory mechanisms of relevance to the understanding and treatment of conditions such as post-traumatic stress disorder and schizophrenia, and a demonstration that schizophrenia risk genes may exert their effects during critical developmental time periods.
Elegant new experimental techniques will allow us to make more discrete and more clinically-relevant genetic alterations, to specifically alter the activity of brain regions, to monitor brain structure and function throughout the animal’s life using imaging techniques, and to assess subtle aspects of behaviour and cognition that are commonly perturbed in mental health conditions. In combination with other avenues of research strength in Cardiff (including genetics, neuroimaging and in vivo and cellular assays), animal model work is likely to contribute to a significantly improved understanding of mental illness, and, hopefully, ultimately, to better access to more effective treatments for common and disabling conditions.
Find out more about animal research at Cardiff University here.
Dr Will Davies receives funding from the Medical Research Council and the Wellcome Trust