Summaries of 2015 research

What animals are we planning to use?

Approximately 90% of the animals used will be wildtype adult rats, the remainder will be genetically altered adult mice (and wildtype controls) from existing strains (i.e. no new genetic alterations will be made).

For what purpose are the animals going to be used?

This project has three main objectives:

• To understand the psychological and biological mechanisms involved in normal emotional and cognitive processes.
• To examine how and why these processes fail in rodent models of psychological disorders.
• To examine how common laboratory techniques (such as injections) impact on laboratory animal welfare and to explore ways in which to minimise these effects.

What will be the harms to those animals and how will these be limited?

The procedures used here are not expected to produce severe adverse effects. The key behavioural observations involve the detailed examination of animals' responses to foods. That said, some of the procedures will be directly aversive (e.g. producing short term stress or nausea). We will use the minimum level of any aversive technique that is consistent with the goals of the study. Some animals will undergo surgery under anaesthesia. Here we will follow veterinary advice to perform these techniques in the safest possible manner and always using analgesia.

What alternatives did you consider before embarking on the use of animals in your research?

Emotion and cognition are only seen in whole organisms. To investigate both normal function, and its disruptions, requires animals because alternative models (such as those based on cell cultures or computational methods) cannot yet capture the complexity of brain circuits. That said, this project is paralleled by research in humans and so only scientific goals that cannot be achieved through research with human participants are included.

What will be the expected benefits?

Psychiatric disorders are a major health burden in the UK (and worldwide). One bottleneck in developing novel treatments is a lack of targets for drug discovery. This project will develop the understanding of emotion and cognitive function in rodents, and how these fail in rodent models of psychiatric disorders. Such outputs will aid the drug development process by identifying targets for new therapeutic techniques.

Many thousands of rodents are used annually in laboratory work based involving techniques such as injections. The welfare impact of these techniques has received little direct scientific investigation, meaning the aversive impacts, and means to minimise them, are not known. This project will provide information about how aversive some common techniques are and about ways to minimise or avoid that harm.

What animals are you planning to use?

Mouse, juvenile and adult, from established genetically modified lines.

For what purpose are the animals going to be used?

Our animals are part of a study to help us understand how retinal cell loss results from inherited defects in mitochondrial genes  and if there are any ways of preventing this.

Inherited optic nerve atrophy (or optic neuropathy) is one of the commonest causes of human irreversible visual loss in the UK. There are currently no medical or surgical treatments available. The diseases lead to visual loss through the disruption in retinal ganglion cell function or loss of these cells. Genes that control the shape and configuration of organelles called mitochondria, which are present in each cell of the body, have been found to be mutated in patients with inherited optic atrophy.

What will be the harms to those animals and how will these be limited?

The mutation of eye disease genes in mice creates minimal suffering, since mice are nocturnal animals with excellent senses other than vision, and they do not rely on good vision to find food or water. The treatments to be used will mostly be agents with prior published safety data, so that doses and toxicity are likely to be avoidable or minimal. The adverse effects could include ocular discomfort and inflammation in the eye. Mice will be monitored and will be withdrawn from any treatment if they display harm.

What alternatives did you consider before embarking on the use of animals in your research?

Investigating the complex processes involved in inherited optic neuropathy, which consists of many different cellular and tissue interactions in the retina and optic nerve, requires animals to establish the outcome of these processes. Animals have to be used because it is not possible to remove tissue from the eyes of living patients who may be tested with new therapeutic agents without any data on their effectives.

What will be the expected benefits?

This project will translate directly to the benefit of people. The research will assist us in finding new treatments and will be of benefit to those with genetic forms of visual loss.

What animals are you planning to use?

For studies that require the use of animals, we will use mouse models only. The majority of studies will utilise inbred mouse strains that are not genetically altered. For some studies where we wish to evaluate the accumulation of virus within a tumour grown in a mouse, we will use mice genetically engineered to have a defective immune system, as this is the only way that human tumour cells can be grown in these animals. For all studies mice will be bought in from commercial suppliers and used at between 8-14 weeks of age.

For what purpose are the animals going to be used?

Our research pioneers the use of a type of virus called adenovirus, which in humans causes mild, non-life threatening infections of the respiratory and GI tracts, as novel therapies for cancer. By removing the disease causing genes, and replacing them with therapeutic genes, we can effectively treat cancer cells in the lab (in vitro). However, treating cancer in animals is hugely more complex compared to in vitro models, as the virus interacts with multiple "off target" proteins and cell types that can cause toxicity and results in accumulation of virus in non-target cell. Our animal studies will therefore help us to understand how the virus interacts with proteins and cells in the whole animal, allowing us to refine and tailor the virus so it selectively accumulates within only the cancer cells.

What will be the harms to those animals and how will these be limited?

The mice will be housed together in social groups. For our studies, we will inject the mice with virus and monitor (non-invasively, using bioimaging techniques) which organs the virus accumulates in. It is therefore anticipated that the animals will not experience any significant discomfort over the course of the experiment. At the end of the experiment, we will ensure all possible organs are retained for analysis, therefore reducing the total number of procedures required.

What alternatives did you consider before embarking on the use of animals in your research?

Before commencing any studies in animals, we perform extensive studies in vitro using cancer cell lines in order to ensure we are only performing animal studies with our lead candidate viruses. Although there are no systems that replace whole animal models, our laboratory is pioneering the use of clinical cancer samples isolated directly from patients, through agreement with Wales Cancer Bank, and access to these valuable samples form an extremely valuable addition to our in vivo studies.

What will be the expected benefits?

Our studies seek to develop viruses that can, once introduce into the blood stream, "seek out and destroy" tumours through selective replication of the virus within the tumour, and/or through the expression of a protein within the tumour that will promote killing of the cancer cell.  This is thus a highly translational project, that we hope ultimately will result in significant clinical benefit to cancer patients, especially in those patients who present with chemotherapy resistant disease.

What animals are you planning to use?

We are planning to use juvenile and adult mice from both wild-type and genetically altered animals. The GA animals are purchased from commercial suppliers and acquired through academic collaborations.

For what purpose are the animals going to be used?

Our animals are part of a study to understand the molecular and cellular basis of social behaviour in pathological and non-pathological conditions. In this context we are particularly interested in Autism Spectrum Disorders (ASD), as they are associated with defects in social behaviour. Animal models of ASD help us to gain access to the molecular and cellular mechanisms responsible for the social deficits observed in the disorder, a type of study almost impossible to achieve in humans.

What will be the harms to those animals and how will these be limited?

During the course of this project the animals will go through various behavioural tests, with a particular focus on the social behaviour. The potential harm that could be done to our animals in this project is an elevation of stress. But sociability is a natural behaviour which can be highly influenced by the stress level. To avoid a rise in stress levels we conduct the different social behaviour tests in the least stressful environment possible (e.g. low light level to no light, quiet room, automated measurements to avoid people in the room). Too many tests could also add to the stress on the animals so we limit the number of tests on any single animal to minimise this.

What alternatives did you consider before embarking on the use of animals in your research?

Understanding the relationship between behaviour and specific cellular and molecular mechanisms necessitates the use of living animals. Nonetheless, before asking questions in vivo we perform in vitro experiments, in particular on neuronal cultures derived from embryonic stem cell lines, where we are able to precisely dissect these specific molecular and cellular mechanisms. This allows us to better understand the results we obtain from our in vivo work and therefore minimize our use of animals.

What will be the expected benefits?

Autism Spectrum Disorders are frequent in the population (about 1% of the western population is diagnosed for autism) and to date no curative treatment exists. The main limitation in the development of therapeutic treatment is our limited understanding of the precise biological mechanisms underpinning the disorders. The knowledge we will develop during this project is precious because it will help unravel potential new targets for the development of therapeutic strategies for ASD, but also for social behaviour deficits in general.

(Differentiated cell culture as an alternative to animals in metabolic studies)

What animals are you planning to use?

Adult rats (only a small number required since each gives several hundreds of millions of the required cells).

For what purpose are the animals going to be used?

Cell culture has both ethical and economic advantages over whole animal work. For cells to be used as effectively as possible their properties in the culture dish need to be as close as possible to how they are within live animals. However, specialised cells that maintain organ specific properties in culture do not freeze well.  This project is dedicated to finding so alternative methods of cell preservation. Different types of cells can then be used in the lab for all manner of research.

What will be the harms to those animals and how will these be limited?

Enzyme inducers are used to raise the number of cells needed and the lowest levels that are effective will be used. Cells are removed under terminal anaesthesia.

What alternatives did you consider before embarking on the use of animals in your research?

With ethical approval, human cells are being prepared and preserved. However, the human tissue varies greatly in quality. This is due to the time after which it becomes available, the age of the patient, life style choices and medication. This means that cell preservation methods are often compromised due to the quality of the starting cells. For this reason we need to use animals to produce the high quality of cells needed.

What will be the expected benefits?

If cell culture is optimised, this should enable the use human cells to replace animals, partly, in the development of medicines. This type of work can reduce animal experiments, facilitate cell transplantation as an alternative to organ transplantation and may be applicable to the preservation of human organs.