1. What it takes to conduct animal research
Research and Innovation Support Conference
What it takes to conduct animal research
Khawar Abbas, University Veterinary Officer
Janet Holt, Senior Business Manager, School of Medicine
Mihaela Lorger, Leeds Institute of Cancer & Pathology
Ronaldo Ichiyama, School of Biomedical Sciences
Ben Woodman 1974-October 2013

2. Overview

3. Overview Office for National Statistics 2011
Infant mortality rate in England and Wales Life expectancy at birth, UK, to
Office for National Statistics 2011

4. Overview
Use of animal for scientific purpose is regulated by the Home Office
Use of animals for scientific purpose (National legislation, local administration and control of animal research), Khawar Abbas
Processes and challenges of costing animal research, Mrs. Janet Holt
Examples of research work being carried out at Leeds University
Dr. Mihaela Lorger
Dr. Ronaldo Ichiyama
Costing issues and general questions – all panel

5. Use of animals for scientific purpose
Research and Innovation Support Conference
Use of animals for scientific purpose
Khawar Abbas

6. Use of animals for scientific purpose
Research and Innovation Support Conference
Use of animals for scientific purpose
(Vivisection)
There is a description, in 500 BC, of cutting the optic nerve and recording the resulting blindness
Claudius Galen (AD 129 – 216), Originator of experimental method, dissected animals in his quest to understand how the body functions.
Waller’s demonstration of the electrocardiogram to the Royal Society (1909)

7. Opposition to vivisection
Research and Innovation Support Conference
Opposition to vivisection
1874 – first successful prosecution under the Martins Act of 1822 brought by the RSPCA against a French Physiologist
Anti-vivisection demonstration in Trafalgar Square, London, 1910

8. Research and Innovation Support Conference
In the UK use of animals for scientific purpose is regulated by the Home Office Animal in Science Regulation Unit (ASRU)
Animal (Scientific Procedures) Act 1986
Directive 2010/63/EU of the European Parliament on the protection of animals for scientific purpose came into force in November 2010.
UK completed transposition 2010/63/EU in in UK legislation in December 2012
ASRU now pressing with implementing revised UK legislation

9. Animals (Scientific Procedures Act) 1986 (ASPA)
What does ASPA cover?
ASPA regulates procedures that are carried out on ‘protected animals’ for scientific research and testing that may cause pain, suffering, distress or lasting harm.
ASPA also regulates the breeding and supply of certain species of animals for use in regulated procedures, and the breeding of animals for the use of their organs or tissues in procedures.

10. What is protected animal? What is Regulated procedure?
ASPA protects all living vertebrates, other than man, and any living cephalopod.
Embryonic and foetal forms of mammals, birds and reptiles are protected during the last third of their gestation or incubation period or from an earlier stage of development if they are going to live beyond the last third of their gestation or incubation period and the procedure is likely to cause them pain, suffering, distress or lasting harm after they have developed to that stage.
A procedure is regulated if it is carried out on a protected animal and may cause that animal a level of pain, suffering, distress or lasting harm equivalent to, or higher than, that caused by inserting a hypodermic needle according to good veterinary practice. This is called the ‘lower threshold’.

11. Under ASPA what licences are required
ASPA has a three-level licensing system:
Establishment Licence: Place at which work is carried out (176)
Project Licence: Programme of work must be authorised (PIs)
2698 (45)
3. Personal licence: issued to those carrying out procedures
(180)
ASPA licences are issued by the Home Office in England, Scotland and Wales and by the Department of Health, Social Services and Public Safety (DHSSPSNI) in Northern Ireland.
Researchers not performing regulated procedures but using animals for tissue after killing them in accordance with Sch. 1 of the Act must also be trained and should be on institutional register maintained by ELH

12. Under what conditions licences are granted?
Establishment Licence:
Suitable facilities for the species of animal(s) to be used. Home Office CoP
Appropriate level of trained staff.
Veterinary surgeon (NVS)
for day-to-day care of animals (NACWO)
those designing experiments and those carry out procedures (PPL & PIL Holders)
Provision of Training and competence officer
Provision of information Officer
Pro-active Animal Welfare and Ethical Review Body (AWERB)
Demonstrable culture of care and commitment to apply 3Rs (Reduction, Refinement and Replacement)

13. Under what conditions licences are granted?
Project Licence: (Valid for 5 years)
Achievable objectives
Comprehensive consideration to 3Rs (Reduction, refinement and replacement)
Comprehensive consideration to cost/benefit analysis
Trained and competent
Availability of suitable facilities and staff
Funding, expertise and other resources available
Demonstrable culture of care through CPD
Personal Licence: (valid for until required)
Trained and competent apply 3Rs at all times
Demonstrable culture of care through CPD

14. Under what conditions licences are granted?
“In determining whether and on what terms to grant a Project Licence the Secretary of State shall weigh the likely adverse effects on the animals concerned against the benefit likely to accrue as a result of the programme to be specified in the licence”

15. Permissible purposes for which Project Licences are granted
(a) basic research;
(b) translational or applied research with one of the following aims —
(i) avoidance, prevention, diagnosis or treatment of disease, ill-health or abnormality, or their effects, in man, animals or plants;
(ii) assessment, detection, regulation or modification of physiological conditions in man, animals or plants;
(iii) improvement of the welfare of animals or of the production conditions for animals reared for agricultural purposes.
(c) development, manufacture or quality, efficacy and safety testing of drugs, and other
substances for one of the aims in (b) above.
(d) protection of the natural environment in the interests of the health or welfare of man or
animals; 
(e) research aimed at preserving the species subjected to regulated procedures; 
(f) higher education/training for the acquisition, maintenance or improvement of vocational skills;
(g) forensic enquiries.

16. Openness http://www.leeds.ac.uk/info/20014/about/25/responsibility
Use of animals in research
The University of Leeds carries out research on animals to improve the health and welfare of human beings and animals, and to provide a better understanding of the animals themselves. It uses animals only when there are no alternatives, and is firmly committed to the principles of replacement, refinement and reduction of animals in research.
Research using animals is driving fundamental advances in understanding, treating and curing a range of health problems including cancer, heart disease, diabetes and mental illness, and continues to enable fundamental advances in our understanding of diseases.
The University will use alternatives to animals wherever possible, such as computer modelling, tissue culture, cell and molecular biology, and research with human subjects. But these cannot yet properly reproduce the complex biological characteristics of man and animals and nor can they replicate the study of wild animals in their natural environment.
All research involving animals is carried out to high standards of humane care and treatment within a strict framework of legal controls. Projects must also be approved by an ethical review committee, and researchers are trained in the ethical dimensions of their work and in standards of animal care, welfare and

17. Declaration on Openness on Animal Research
The life sciences sector is at the forefront of developing ground breaking treatments and cures which transform the lives of humans and animals. To do this we need to increase understanding of normal biological functions and disease. Where possible,
we use cells grown in a lab, computer models and human volunteers. When this isn’t possible, research may involve animals.
When we need to use animals, we strive to reduce the number needed, and seek to develop viable alternatives.
08/11/2018

18. Openness
Guidelines for the welfare and use of animals in cancer research British Journal of Cancer (2010) 102, 1555–1577.
In order for scientists to understand how cancers develop and spread throughout the body and to discover new and more effective ways to diagnose and treat cancer, it is necessary to carry out research on live animals. Animal studies (over 95% of which are conducted in mice) are essential to understand the complexities of the fundamental processes that underpin cancer within living organisms. They are also required by regulatory authorities before any trials of new drugs can be tested in humans. Animal studies are only performed after every feasible test has been conducted on cancer cells in the laboratory and where no alternative exists. Adverse effects on the animals are minimised as far as possible. However, it is a source of concern for society and research scientists alike that, as we cannot replace all animal experiments in the immediate future, the highest standards of welfare are upheld.

19. UoL Designated Animal Facilities
Central Biomedical Services, Garstang Building.
St. James’s Biomedical Services, Clinical Science Building
Institute of Psychology Closed October 2013
University Farm Part of farm was designated but no longer
but some work continue as POLE
Work being carried out in the wild as POLE.
Several other designated rooms in Garstang, Worsley , LIGHT buildings and in LGI Clarendon Wing NSEP/NOH

20. Use of animals under ASPA at the UoL in the last 5 years

21. Major achievements by UoL scientists
A. Cancer development, mapping, diagnosis and treatment
Mouse models for tumour stem cells and anti-tumour efficacy studies
Gene function in tumorigenesis (leukaemia, sarcoma, lung, prostate and breast cancers)
Mechanisms regulating growth of brain metastasis
Renal Cancer Biology and Therapy
Immune and Biological Therapies for Cancer
New approaches to radiosensitisation of brain or spinal tumour
The potential for new treatments, or strategies for developing them, to address problems of cardiovascular disease and cancer in people.
B Cardiovascular studies
Mechanistic basis of cardio-metabolic disease. Diabetes and Cardiovascular Disease
cardiovascular and respiratory function in disease
Right Heart failure
Statin effects on heart and skeletal muscle
Molecular mechanisms regulating normal and disease cardiovascular physiology

22. Major achievements by UoL scientists
C. Applied research:
Biocompatibility of Tissue Engineering Scaffolds
Biological Response to Prosthetic Nanoparticles
Wound healing
D. Neurological /psychiatry/anxiety /drug addiction research
To evaluate potential novel pharmacological therapies for the treatment of Alzheimers’s disease
Mechanisms and treatment of anxiety
Behavioural Neuroscience of Drug Addiction
Neurobehavioural disorders: causes and therapies (autism and schizopherenia)
Neuronal function and psychiatric disorders (autism and schizopherenia)
Genetic Causes of Neurological Disorders (mainly brain disorders e.g. Ataxic cerebral palsy , Optic nerve hypoplasia)

23. Major achievements by UoL scientists
Surgical models
Development and testing of a novel cardiac assist device.
Minimally Invasive Surgical Technology
Surgical treatment of congenital bladder defects in neonate
Surgical treatment of congenital urethral abnormalities in male neonate
Identifying time-sensitive biomarkers that correlate with the development of abdominal sepsis.
Ecology and conservation
Disease ecology in wild bird populations
Bat conservation
G. Pain research
Molecular mechanisms of pain
Rehabilitation of patients after spinal cord injuries
Farm animal research
Effect of food manipulation on farm animal production (pigs and chicken)

24. Cost of animal research
Expensive Expensive Expensive
Facilities: Must meet HO CoP Charged at premium rate
Animals: High cost
Maintenance of animals: Food/water/bedding/cages/environmental enrichment
Procedures: To carry out procedures many consumables are needs.
Licences: Each personal licence costs £230/year
Presently this cost is met by the centre (not in many other universities)
This gives our staff at least some relief
Surcharge(s): 10% CBS surcharge on all consumables, animals ordered through CBS
What are other hidden costs? Comparison with other institutions
Level playing field for our researchers?? How? ?

25. Processes and challenges of costing animal research
Research and Innovation Support Conference
Processes and challenges of costing animal research
Mrs Janet Holt
Senior Business Manager
SCIF, School of Medicine

26. Costings
Expensive
Specialised work
MRF (Major Research Facility for RCUK)
Research Grant Activity

27. MRF Costs
Staff
Running Costs
Equipment
Depreciation
Estates
Usage (Bench Marking)

28. Costing Process for KRISTAL
Researcher
Facility
FRO
Business Manager

29. Challenges for Facility and Business staff
Ensuring:
Correct account is given
End date of grant is known
Work is completed by grant end date

30. DI rather than DA costs Difficult to agree regular charges in advance
Dealing with in vivo rather than in vitro work
Audit trail linked to charging

31. External work vs Internal
External work is easier to manage financially but the facility is built for internal usage
Objective is to find research users with needs to take up capacity and help maximise cost effectiveness

32. Challenges within the facility
Barrier requires minimum number of staff
CRB and Home Office approved staff only
Agency staff required for cover

33. Challenges to Researchers
Finding necessary funding
Getting work done in time
Challenging nature of work

34. Leeds Institute of Cancer and Pathology
Research and Innovation Support Conference
Development of therapies for brain metastases in pre-clinical mouse models
Mihaela Lorger
Leeds Institute of Cancer and Pathology

35. Metastasis
Alberts et al., 2002

36. Metastasis
From Cancerfacts.com
From Cancerfacts.com

37. Brain metastasis
Brain metastases occur in % of all cancer patients and originate mainly from lung cancer, breast cancer, and melanoma
Symptomatic brain lesions develop late during the progressive metastatic disease and their frequency is increasing.
Current clinical therapies include surgical resection combined with the whole-brain radiation and stereotactic radiosurgery
Irrespective of treatment, the patients with brain metastasis have a very poor prognosis - median survival time below 9 months
Challenges for the treatment of brain metastases:
- shielded by the blood-brain barrier
- very often resistant to standard treatments

38. Use of blood cell progenitors for delivery of therapeutic agents to brain metastases
Release into blood circulation
Tumour
BONE MARROW
Source of blood cell progenitors
BRAIN
Infiltration of white blood cells into brain tumours
BLOOD

39. Use of blood cell progenitors for delivery of therapeutic agents to brain metastases
Tumour cells
Blood progenitors
Introduction of therapeutic genes into blood cell progenitors
gene for green fluorescent protein
Animal model of brain metastasis

40. Use of blood cell progenitors for delivery of therapeutic agents to brain metastases
Tumour
White blood cells

41. Feasibility of rapid translation into the clinic:
Use of blood cell progenitors for delivery of therapeutic agents to brain metastases
Goal:
Transplantation of genetically modified blood cell progenitors expressing different therapeutic agents and delivery of agents to brain metastases
Feasibility of rapid translation into the clinic:
Clinical trial with a successful outcome using genetically modified blood cell progenitors has been recently performed in patients with X-linked adrenoleukodistrophy, a severe brain demyelinating disease (Cartier et al., 2009)

42. Problems with the current costing system for animal research at the UoL
High costs of animal research at the UoL:
- prices for mice are in general high in Europe as compared to USA
wild-type strains (C57Bl/6, BALB/c) are nearly 2x as expensive at SBS as compared to Charles Rivers Laboratories UK
→ difficulties to justify use of animals bred at UoL in grant applications where the costs should be kept as low as possible;
→ high animal costs mean that less money can be allocated for salary and consumables; this may negatively impact the feasibility of the planned projects;
Transparency in pricing:
some funding agencies require justification for animal prices
basis for costing is not available from SBS
inclusion of indirect costs in animal prices would not be acceptable to funding agencies that provide indirect costs in addition to research costs;

43. Acknowledgements
Nora Rippaus
Jennifer Williams
David Taggart