Animals in research

In 2006, the Institute opened the Research Support Facility (RSF). The mission of the Institute, and the RSF, was to make a vital contribution to understanding and treating of major human health problems including cancer, heart disease, diabetes and mental illness. The building was designed to facilitate the production of genetically modified mice at scale and under standardised conditions. These animals could then be studied for unusual traits, health conditions, or used to validate scientific concepts, that could ultimately lead to clinical therapies due to their translatability. We also sought to increase the understanding of animal disease. In order to allow this research to take place, we needed to use animals for some of our research.

In September of 2021, the RSF concluded its use of animals for research, and closed its doors. During its 15 years of operation, it supported numerous scientific programmes that helped advance the understanding and application of treatments for many human diseases. Upholding high standards of care and welfare in regards to the animals used, while supporting the scientific need for their use was a vital balance to maintain.

The Institute would like to thank all the animal technicians, technical support staff, managers and researchers who strived to maintain this balance, developing and applying refinements in animals care and use, seeking out alternatives where possible, and producing valuable scientific outputs. Without these members of staff, the RSF would not have been the success it was.

Research using animals at the institute was never undertaken without due consideration and justification.

All proposed research using animals required approval from the Institute’s Animal Welfare and Ethics Review Body. When planning the research programmes our researchers were required to fully explain the purpose of the research, justify the use of animals and demonstrate they had applied the principles of the 3Rs – Reducing the number of animals to be used; Refining experiments to improve the quality of the animals’ lives; and Replacing the use of animals through alternative techniques.

If you would like ask us more about the research we performed using animals you can contact us; animalsinresearch@sanger.ac.uk

Animals (Scientific Procedures) Act

In addition to gaining Sanger’s authorisation, all research using animals must comply with the Animals (Scientific Procedures) Act 1986 Amendment Regulations (2012), also known as ASPA.

Any practical procedure performed on an animal and covered by ASPA must comply with three conditions. It may only be undertaken by a researcher holding a Personal Licence (PIL); the work must be part of a programme of covered by a Project Licence (PPL); and must take place in an institution with an Establishment Licence (PEL). To handle or work with animals, researchers are required to attend courses, including those accredited by the Home Office, and sign a Code of Conduct detailing the behavioural standards of the staff and the responsibilities to the animals in their care. The Institute also assessed the skill and competency of all animals’ users in the procedures they intended to undertake using animals.

The Animal Facility

Our animal facility was designed to facilitate animal welfare, which took priority over any other considerations. When opened in 2006, the RSF was a prime example of a state-of-the-art animal facility where animal welfare was a core design feature

During the operational life of the RSF, we used the highest standard of caging and husbandry, as well as methods to breed the right amount of mice required to perform studies. The RSF also benefited from a number of refits and upgrades to equipment and rooms, ensuring that the building was fit for purpose for the animals and the new breakthroughs in our understanding of genetics

The staff who worked in the facility were committed to continually improve standards and they had regular open meetings to discuss issues and to develop strategies. These strategies enhanced our care of, and provision for, the animals and the quality of our science, and in November 2021, the RSF team was nominated for a Papin Prize in the category of Core Facility Research at the UK Higher Education Technician Summit.

The Institute’s animal facility operated 24 hours a day, 365 days a year. Trained and qualified staff, supported by the Institute’s Named Veterinary Surgeons, carried out animal health monitoring around the clock. All staff who interacted with the animals were responsible for promoting a culture of care. We respected the animals entrusted to us and protected their welfare to prevent no unnecessary pain, suffering or harm was inflicted upon them.

In addition, we regularly audited our facilities and working practices, and had a continuous programme of training and assessment of the competency of our staff.

Concordat on Openness on Animal Research

The Concordat on Openness on Animal Research in the UK, which has been developed by Understanding Animal Research in collaboration with leading research institutes, aims to broaden understanding and acceptance of humane animal use in biomedical research, and calls for research institutes to be transparent with the public about all aspects of research conducted using animals.

As former signatories to the Concordat on Openness on Animal Research in the UK, we worked hard to engage with interested groups on all our science, and our participation in the Concordat strengthened this approach on a topic which can elicit wide debate and strong opinions.

The Concordat consists of four commitments:

• To be clear about when, how and why we use animals in research
• To enhance communications with the media and the public about our research using animals
• To be proactive in providing opportunities for the public to find out about research using animals;
• To report on progress annually and share our experiences.

We had a series of actions that we were required to take under each of the commitments and report back to Understanding Animal Research. Our activities included:

• Explaining our work with animals through our media work, including being clear where animal or human cells are being studied
• Welcoming journalists to the Institute animal facilities
• Working on student activities in the UK and abroad
• Providing training and support to spokespersons
• Providing images and other resources to enquirers.

Governance

The use of animals in research is monitored by independent inspectors from the Home Office, who would routinely come to the Institute to inspect our facilities, the condition of the animals and the work being undertaken. In addition, the Institute developed policies and guidelines monitoring all its research and a public statement of what it expected from any member of staff working with animals.

In compliance with the law, the Sanger held and supported the necessary licensing authorities to permit research using live animals;

• A Home Office Establishment Licence – this enabled research using live animal models to take place at the institute.
• Home Office Project Licences – these outlined programmes of research and authorised specific types of procedures to be carried out on live animal in line with the research requirements.
• Home Office Personal Licences – these allowed individuals to perform regulated procedures, as authorised within the Project Licence, on live animals. Any individual that held a Personal Licence had to be trained and assessed as competent in all procedural techniques they wished to apply to an animal before they were authorised to perform their work.

Each of these three types of licence had statutory obligations applied which must be fulfilled. In addition, all members of staff working live animals at the Sanger Institute were obligated to sign the Institute’s code of conduct, which was strictly enforced.

Before a researcher could start a new research project using animals they had to write an application for a project license that could run up to, but for no longer than, five years. This application would describe;

• Their research goals,
• The benefits of the research,
• The number of animals they plan to use,
• The procedures they will use on the animals,
• How they have applied the 3Rs to the design of their research.

Each proposed procedure had to be classified as mild, moderate or severe depending on how they were expected to impact on the animal’s welfare, and must be justified. These classifications are strictly defined by the Home Office, and the Institute and all users of live animals are legally bound to observe these classifications. The result of procedures must not have exceeded the severity limit outlined in the research proposals. At the Sanger Institute, over 80 per cent of our procedures were classified as mild, with less than 0.5 per cent severe.

All applications are reviewed by the Institute’s Animal Welfare and Ethical Review Body (AWERB) which is made up of scientists, statisticians, the Establishment Licence Holder, staff who work in the animal facility, Named welfare experts including a veterinarian, and internal and independent external lay members. The applicant must present their work to the AWERB and answer their questions. The AWERB’s priority is to consider the ethics of the research being proposed and perform a harm-benefit analysis to determine if the level of severity an animal cold experience is justified to produce the scientific output in terms of benefit to overall society. They  may advise the establishment licence holder to turn down an application, ask for revisions to improve welfare, or approve the research. Once a decision is made the establishment licence holder is responsible for endorsing an application with their support before it is submitted to the Home Office for review, and hopeful approval.

All research programmes are regularly reviewed to consider the value of the science we do and whether it justifies the use of animals. The Project Licence holder(s) were required to retrospectively report back to the AWERB on the progress of their project during year 3 and at the end of the fifth year of their licence. A failure to adhere to the conditions of the licence, a major deviation from the numbers used or overstepping the authorised severity could result in cancellation of a licence and sanctions from the Home Office, including criminal prosecution where appropriate.

The 3Rs

The principles of Replacement, Reduction and Refinement (the 3Rs) are embedded in European and UK law. The 3Rs are not simply a way of using fewer animals in an experiment or using animals less often, they are a driver for innovations and developing new tools.

It is a key requirement that all applications for Project Licences show how the 3Rs have been applied to the experimental design. Researchers at the Sanger Institute not only did this, but have were very active in developing the 3Rs. They undertook a variety of approaches including developing new non-animal systems and models, refining experimental techniques, and developing new technologies that reduced the number of animals needed for breeding.

As an example, staff at the Institute actively designed and implemented the Experimental Design Assistant (EDA) whose development was led by the NC3Rs. This freely-available, online tool guides researchers through the design of experiments that use animals and ensures that they use exactly the right number of animals so that results are statistically significant without using more than is necessary.

We actively encourage collaboration and the sharing and archiving of animal types (such as a particular group of animals carrying a unique genetic modification) to avoid repetition of animal experiments, thereby reducing the number of animals used around the world.

The 3Rs refinements are not only focussed on the application of procedures, or refinement of scientific techniques, but also refinements in approaches to animal care and welfare monitoring. In October 2021 the RSF and NC3Rs published and educational package on the care and welfare of mice used in research relating to a common husbandry concern, malocclusion.

Alternatives

Although it is not possible to completely remove the need for animal models altogether, the Sanger Institute developed a number of alternatives to the use of animals in some areas. These alternatives are able to significantly reduce the number of animals needed, or are able to replace animals in one step of the scientific and translation process, and in part contributed to the decision of the Institute to focus on these emerging areas of research.

Open Targets

Open Targets is an innovative collaboration between EMBL-EBI, the Wellcome Sanger Institute, GSK and Biogen, which seeks to accelerate drug discovery using genome-scale experiments and analyses. Drug discovery is a highly challenging process and with a relatively low success rate. Traditionally, animal models have played a key role in the process of validating possible drug targets. The goal of Open Targets is to transform the drug discovery process by predicting whether a drug acting on a particular target is likely to provide therapeutic benefit, more effectively and much earlier in the drug discovery process than is currently possible.

The Open Targets have developed an open-access informatics platform (www.targetvalidation.org) that allows users to start from the standpoint of the disease or the target. Users can ask what might be likely targets for a certain disease, or what diseases might be associated with a particular target. The platform works by combining information from a range of biological data sources which are then scored to reflect the strength of an association between a target and a disease.

In order for drugs to be approved and licensed for use in humans, their safety and efficacy must still be tested in animals; however the Open Targets programme allows researchers to efficiently begin validation of targets using information from existing biological data and human disease models thereby reducing the need for data from animal models in the earlier stages of drug development.

Organoids

Before any research is ever carried out in animals, preliminary data must be gathered in order to provide evidence and justification for moving into animal models. For many researchers much of this evidence is gathered using cell-lines. Cell-lines are cultures of individual cell types such as white blood cells or liver cells, for example. They are cheap and easy to grow and use, however they often contain large genetic differences from cells found in the body and they also only grow in 2D layers. This means they are poor models of the three dimensional organs they are derived from.

The Sanger Institute has been heavily involved in the development of organoids – small clusters of cells that grow in 3D so they more accurately mimic the behaviour of human tissue than traditional cell-lines.

Many of the organoids created at the Sanger Institute have been created from tumours of patients with cancer. This means they carry all the genetic mutations which are unique to the individual tumour making them identical to the tumour. By building up a collection of organoids it will be possible to test a range of existing and new therapies on multiple tumours from the same cancer type and connect drug efficacy with the mutations present in the tumour, offering the potential for more tailored treatment in the future.

Although unable to replace the use of animals, organoids provide an additional screening step between cell-lines and animal models meaning fewer potential therapies and interventions will move on to testing in animal models and a higher rate of success in those animals.

This research was awarded a prestigious 3Rs Prize by the National Centre for 3Rs. The NC3Rs Prize is awarded to highlight an outstanding original contribution to scientific and technological advances in the 3Rs in medical, biological or veterinary sciences published within the last three years. The prize is part of our commitment to recognise and reward high quality research, which has an impact on the use of animals in the life sciences.

Genome Editing in induced Pluripotent Stem cells

Researchers at the Sanger Institute traditionally used mouse models in order to understand which genes are required for development of the embryo into the adult. By “knocking out” different genes, they were able to determine which genes are required for the development of stem cells all the way into tissues in the adult mouse. This helped researchers understand which genes in humans are vital for human development as mice and humans share many genes. However, the methods for deleting genes or turning them off in mice were difficult, expensive and each gene could take months, making such a project hugely expensive and time-consuming.

The development of the CRISPR-Cas9 technology, which allows precisely targeted changes to be made easily and cheaply to genomes of many species, has allowed our researchers to make genetic changes to human induced Pluripotent Stem (iPS) cells grown in culture. When grown in the right conditions iPS cells can develop into different human tissues. CRISPR-Cas9 allows researchers to switch off specific genes, in a way that previously was not possible at the scale we work at. The development of a large-scale, high-throughput approach means some research programs no longer use animals.

Scientists' views on using animals in research

The decision to use animals in research is not an easy one for researchers to make. When asked about their work with animals in research, Institute researchers and technicians talked about the importance of their work developing the standards of care and their refinement of techniques and experiments to minimise suffering. They also expressed pride in their work and the value of their research, which contributes to the Institute’s mission of improving health worldwide.

Animal Technician

“As an animal technician I get to work hands on with the animals and the science being undertaken. Not only do I gain first-hand exposure to the exciting developments in knowledge and understanding of varying human diseases, I also take immense pride in the work I do. Knowing that the welfare is at the forefront of our decision making when assessing the harm-benefit of an animals life experience, and that I can help ensure no animal experiences unnecessary pain, suffering, distress or lasting harm when in my care, makes what I do worthwhile”.

“I have the privilege of supporting the research staff who carry out the experiments and who strive for cures and further understanding of diseases that affect many people worldwide. It is good to see that the research is well planned and considers the 3Rs, in regard to animal use. I also work with the Animal Technicians who are advocates for the animals and can honestly say that that they are true professionals – ensuring that the animals are very well cared for.”

Project Licence Holder

Every research project using animals must have a licence and licence holder. Only senior members of Institute staff are able to hold these licences and they are legally responsible for all research that happens under that licence. Obtaining a licence is a serious undertaking that requires time and commitment from researchers. Most researchers find the process of applying for a Project Licence challenging but they recognise the rigour of the application process and the level of responsibility that holding a Project Licence brings. Researchers are frequently confronted by the ethical implications of the work they do and the Project Licence application process gives them the opportunity to consider these issues and decide how and when to use animals.

“Running research programs which work with animals is more complicated than most people think, and I’ve found that often includes the scientists that don’t use them. At every stage, there are checks and balances to make sure that the work to be carried out meets the criteria for being able to perform any study. From ethical reviews, to ensuring staff competency, making sure that the legal, regulatory and welfare requirements are in place as well as correctly designing and implementing the study, all these things need to be in place even before any animal is touched.”

“Some people may consider that the barriers to being able to work with animals are too high and that science is inhibited by regulations and bureaucracy. My view is that these safeguards have an essential role to play. Appropriate barriers should be there to prompt the simple question, do you really need to use animals? The people I know that work with animals all want what is best for the animal but balanced with the scientific value that can be derived from the study. That tension between the value of using the animals and the welfare consequences for it runs to the heart of whether it is ethical to perform animal experimentation and is something that we should continuously evaluate when working with animals.”

All research using animals must be approved by the Animal Welfare Ethical Review Body (AWERB). The AWERB committee is made up of Faculty, the Establishment Licence Holder, a statistician, internal and external lay members, ethical and regulatory advisers, and staff from the animal facility. The committee reviews all applications for new Project Licences and they review the progress of Project Licences already underway. Project Licence holders are expected to present their applications or progress reports in person to the AWERB and will take into consideration all comments and recommendations made by AWERB.

“Sitting on the Institute’s Animal Welfare Ethical Review Body (AWERB) has allowed me to see how hard researchers work when designing their experiments and how dedicated the technicians are to the care of the mice and zebrafish. Not only do researchers design experiments that answer important research questions but they also include implementation of the 3Rs, consider the welfare of the animals and decide whether the research is good enough to justify using animals.”

“All researchers applying for a project licence come in front of the AWERB committee and are questioned on their entire proposal by statisticians, other researchers and by the animal facility staff who care for the animals. It’s a long and exacting process but the researchers are held to account and it means better care for our animals and improved science. There have been times when we have said no to researchers and I’m proud of the fact that the AWERB holds everyone accountable for their work.”