2013

NC3Rs Gibbs Building 215 Euston Road London NW1 2BE

T +44 (0)20 7611 2233 F +44 (0)20 7611 2260 [email protected] Annual Report twitter: @nc3rs The material used in this publication is derived from sustainable and renewable sources. The Paper is FSC® and ISO14001 accredited. www.nc3rs.org.uk All inks used are vegetable based and all www.crackit.org.uk pulp is Elemental Chlorine free (ECF) Pioneering Better Science 02 | 03 Foreword

Over the last year, we have concentrated on our key strengths in bringing communities together, in fostering new science and innovative problem solving, and establishing new collaborations. This report summarises some of our highlights from 2013.

We have demonstrated that first class science and the 3Rs can go hand-in-hand and as a result we have seen demand for our resources increase again in 2013. We have responded to this with new funding opportunities to support 3Rs infrastructure and networking, and new strategic partnerships, including an exciting collaboration with the Technology Strategy Board to commercialise 3Rs technologies. In 2013, we committed £8 million for research and training, worked with 48 companies from across the globe on data sharing initiatives and increased the number of journals endorsing our reporting guidelines from 176 to 335.

Our 3Rs strategy addresses major scientific and business challenges including translating research into economic growth, tackling serious diseases and reducing drug attrition. At its core is a commitment to minimise animal use and suffering and it is this which makes the NC3Rs unique.

Animal research will continue to be one of the most contentious issues in science. This was certainly the case in 2004 when the NC3Rs was launched. Since then, as a result of our work, there has been a shift in the level of scientific engagement in the 3Rs and the ethos around animal research has started to change. The key challenge now is maintaining this momentum at a time when budgets are tight.

The landscape continues to evolve and in 2014 we are planning a ten year forward look to examine the role of the NC3Rs in an environment that is very different to where we started. We will continue to work hard to ensure that the NC3Rs stays at the forefront of delivering a 3Rs agenda that addresses societal concerns about animal use and supports the health and wealth of the nation.

Dr Vicky Robinson, Chief Executive Professor Stephen Holgate CBE, Board Chair Foreword 1 04 | 05 Highlights

New Infrastructure for Impact funding scheme launched

In 2013 we launched the Infrastructure for Impact funding scheme. This funds equipment, networking and data sharing, complementing our existing research-focused funding mechanisms. Four awards were made totalling £1.3 million. The awards include a systematic review and meta-analysis resource to help improve the design of animal studies; a database for sharing materials and knowledge across the UK breast cancer research community to avoid unnecessary repetition of in vivo studies; multi-centre and multi-user imaging for cancer and trauma studies; and an online teaching and training resource for refinement (for example, the use of anaesthesia, and recognising pain and distress). In total we received 16 applications for the competition, making the success rate for the scheme 25%.

We also committed £2.3 million for project and pilot study grants. A total of 14 awards were made; five project grants and nine pilot study grants with success rates of 11% and 22% respectively of the total applications received. 79% of the grants awarded focus on replacement, 7% on reduction and 14% on refinement. The awards cover a wide range of areas from applying the 3Rs to malaria infection studies in mice to using the fruit fly to investigate the role of glial cells in neurodegeneration. A full list is given in the Annexes.

In November, we published the second review of our research portfolio, focusing primarily on project grants. In the report, we illustrate the impact of the awards we have made in terms of the 3Rs, new scientific and technological discoveries, and policy and regulatory changes. We provide quantitative and qualitative metrics of impact across all grants, including a bibliographic analysis and detailed case studies. 2 Highlights 06 | 07 Highlights

New funding for the CRACK IT Challenges competition

CRACK IT Challenges is a collaborative disease. The other four Challenges focused funding competition designed to address on cardiac toxicity, nephrotoxicity, infectious scientific or business needs with a 3Rs diseases and chronic pulmonary inflammatory theme by connecting the industrial, academic disease. A list of the Challenge sponsors is and small and medium-sized enterprise given below. The competition was run through (SME) sectors. The focus is on developing the Technology Strategy Board’s (TSB) Small marketable products or processes. Business Research Initiative with a total Challenges are posed by sponsors and budget of £7 million. This includes £2 million are put to the scientific community for from the TSB, a doubling of its contribution solving. Funding is provided by the NC3Rs compared with the previous year. with sponsors committing co-funding and/ or in-kind contributions such as access to A total of 32 applications were received for compounds and equipment. The competition the Phase 1 competition. Seventeen awards is run in two stages: Phase 1 supports six were made, totalling £1.6 million, with almost month proof-of-concept studies of up to half of the successful teams including one New funding to support £100k, with a maximum of four awards made or more SME partners. Decisions on Phase 2 per Challenge. The awardees subsequently awards will be taken in July 2014. the CRACK IT Solutions compete for Phase 2 funding of up to £1 million per Challenge. For both phases, This year also saw the award of Phase 2 awards take the form of milestone-driven funding for the 2012 CRACK IT Challenge technology partnering hub contracts rather than grants. competition, with co-funding from the Medical Research Council (MRC). Awards totalling In 2013, there were five CRACK IT Challenges £1.4 million were made for two of the four and seven sponsors. This included for the first Challenges; PREDART, the development of time sponsorship from a charity, Alzheimer’s non-mammalian assays for developmental CRACK IT Solutions is a technology The scheme supported collaborations Research UK, who provided £350k of co- and reproductive toxicity, and Rodent partnering hub designed to provide a platform between academia and industry, SMEs funding towards a Challenge to develop a Little Brother, a non-invasive approach for for researchers and companies to showcase and academia, and between SMEs. A list human stem cell-based neuronal assay for measuring the activity and behaviour of technologies and products with 3Rs potential. of awards is provided in the Annexes. predicting the efficacy of drugs targeting mice in their home cage. The aim is to identify new partners to help tau, the protein which forms the hallmark further develop, validate and adopt the One of the technologies showcased and neurofibrillary tangles observed in Alzheimer’s A list of awards is provided in the Annexes. technology being showcased. In 2013, five supported with a CRACK IT Solutions new technologies were promoted through grant was the use of the social amoeba, Title Theme Sponsors CRACK IT Solutions, three from SMEs and Dictyostelium discoideum, as a screen two from academia. for palatability testing in pharmaceutical UnTangle Alzheimer’s research Alzheimer’s Research UK, Janssen, Lilly development. The funding was used to To catalyse collaborations between Solution provide proof-of-principle that this non- InPulse Cardiotoxicity GlaxoSmithKline providers and potential end-users, a new animal model could correctly identify aversive Inhalation Translation Chronic pulmonary GlaxoSmithKline, Huntingdon Life funding scheme was introduced with awards compounds. Based on this, a collaboration inflammatory disease Sciences, Pfizer of up to £30k over 12 months. In 2013, five to progress the work is planned between Nephrotube Nephrotoxicity GlaxoSmithKline, Pfizer, Roche CRACK IT Solutions grants totalling £150k Professor Robin Williams (Royal Holloway, were awarded, with an additional £112k of University of London) and GlaxoSmithKline, Virtual Infectious Infectious diseases NC3Rs external funding secured from end-users which is scheduled to start in 2014. Disease Research and Solution providers. 08 | 09 Highlights

New cross-funder collaboration to New research strategy for the 3Rs commercialise 3Rs technologies potential of imaging technologies

One of our main objectives since the In November, a £4 million call funded by Imaging technologies, such as magnetic Based on the workshop, key research NC3Rs was launched has been to support the NC3Rs and TSB plus the Engineering resonance imaging, have been used themes were identified as part of a 3Rs a pipeline of 3Rs science and technology. and Physical Sciences Research Council effectively across a range of disciplines strategy to enhance the use of preclinical This has provided the foundations for (EPSRC), the Biotechnology and Biological and therapeutic areas to reduce and refine imaging and address current technological the next step – to support innovation and Sciences Research Council (BBSRC) and the the use of animals by allowing longitudinal limitations. The six themes formed part of entrepreneurship by taking new models, Defence Science and Technology Laboratory, studies to be performed in the same a £1 million strategic call launched by the tools and technologies from the research was launched for business-led feasibility animals and earlier humane endpoints to NC3Rs in August which included tracking base through to commercialisation. During studies on how non-animal technologies can be adopted to minimise suffering. There is cell fate and distribution, 3D gene expression 2013, we worked with the TSB on a new be applied and commercialised in the UK. still, however, an opportunity to maximise profiling, imaging bioengineered tissues, collaboration to explore the market potential The competition is open to large companies the 3Rs benefits of imaging, particularly molecular imaging of the biodistribution of of non-animal technologies and the economic and SMEs, with academic partners where with regard to replacement. drugs including macromolecules, improving impact for the UK, reflecting the changing they strengthen the collaboration. Feasibility sensitivity and resolution, and phenotyping landscape for pharmaceutical and chemical projects of up to £250k will be funded. In June, we hosted a joint workshop with genetically modified mice. development and the opportunity for the UK To support the competition, the NC3Rs the TSB-funded Electronics, Sensors and to build on its strengths in this area. and TSB have hosted regional consortia Photonics Knowledge Transfer Network The competition closed in October with 26 building workshops across the UK. The (ESP KTN) to bring together the UK’s applications submitted. Funding decisions As part of this process, the TSB compared first awards will be made in May 2014. The preclinical imaging community – biologists will be made in March 2014. the business potential of over 150 emerging competition forms part of a larger initiative and imaging technology manufacturers – technologies. To help build the case for with the NC3Rs and TSB continuing to to explore the development of preclinical non-animal technologies, the NC3Rs and collaborate with other funders on a national imaging to advance the 3Rs. This was the TSB jointly hosted two workshops to discuss programme on the business development first meeting of its kind involving experts with experts from a range of sectors the of non-animal technologies. from across the preclinical imaging modalities. disruptive potential of technologies such as microfluidics, 3D organ cultures and mathematical modelling. This led to non- animal technologies being selected as one of four new areas for investment by the TSB through its ‘Emerging Technologies and Industries’ programme. 10 | 11 Highlights

New human tissue initiatives New recommendations to reduce 11 20 to replace7 animal use the use of recovery animals 11 3

5 25 12 13

13 9

In May, together with the Medicines and community. This has identified regulatory and During 2013 we completed the analysis We have focused on study designs and the Healthcare products Regulatory Agency supply issues as key barriers to use and these of data collected as part of our joint impact the inclusion or exclusion of recovery (MHRA), we convened an expert working will form the main focus of the group in 2014. programme with the MHRA to consider animals has on internal and regulatory group to explore opportunities for the opportunities to reduce the use of recovery decisions. We have analysed a large data 2. Human tissue (p. 11) wider adoption of human tissue-based Our expert working group on asthma models animals in pharmaceutical development. set provided by 22 companies on 137 approaches to replace animal use in the has also been investigating the use of human compounds (including 53 biologicals and safety assessment of new drugs. The working tissue to replace animal use, as part of a Recovery animals – rodents, dogs and 78 small molecules) and 259 studies. This 11 group has 28 members,20 including 14 from collaboration with Asthma7 UK, the Human non-human primates – are used in many showed that there was wide variation in when pharmaceutical companies and seven from Tissue Authority and the UK Respiratory toxicology studies to determine whether it is and why recovery animals were included, 11 international regulatory agencies. The initial Research Collaborative.3 A similar approach possible to recover from any adverse effects with the number of recovery animals used priority for the group has been to assess the has been taken with an initial survey being caused by the drug being tested. A global per compound ranging from zero to over One-month 5 25 rat toxicity current12 use of human13 tissue through a survey conducted to assess the extent of current expert working group with representatives 100. The analysis has provided the basis for Inadequate supply and characterisation of tissues of the internationalInadequate supply safety and characterisation pharmacology of tissues use and perceived barriers. from 32 organisations, half from Europe and evidence-based recommendations to support study Perceived regulatory acceptance Perceived13 regulatory acceptance 9 half from the USA, including pharmaceutical a change in company practice and regulatory Practicalities of using fresh tissue/stem cells Practicalities of using fresh tissue/stem cells and biotechnology companies, contract requirements to allow a reduction in the use research organisations and regulatory of recovery animals for studies conducted Obtaining correct ethical consent documentation Top six perceivedObtaining correct barriers ethical to consent uptake documentation authorities, has facilitated data sharing with prior to first-in-man clinical trials. The Inter-individual variability of humanInter-individual tissue approaches variability Drivers for human tissue Logistical issues e.g. transport, shelf-life in safetyLogistical pharmacology issues e.g. transport, shelf-life use in safety pharmacology the NC3Rs acting as the ‘honest broker’. recommendations will be published in 2014.

!"#$%&'(%)*& Variation in the use of recovery animals

)*+,-$+./012$,30$+.30$ NO YES 30104,-5$ 2. Human tissue (p. 11) 101+ 2 "(#$ 14 13 6..3$730/89:45;$.<$,-8+,1$ 76-100 5 '#$ +./012$

20 =,9>$.<$2*85,?10$,-8+,1$ 51-75 "&#$ VE RY !"#$ +./012$ OMPOUND 25-50 51 One-month @.25$ rat toxicity 1-25 34 "%#$ Inadequate supply and characterisation of tissues InadequateHuman supplymodels and are characterisationmore relevant of tissues Human models areInadequate more relevant supply and characterisation ofHuman tissues models are more relevant study Perceived regulatory acceptance Poor predictivty of animal models Poor predictivty of animal models Poor predictivty of animal models A5B03$ Perceived regulatory acceptance Perceived regulatory acceptance 25

NUMBER OF RE CO ANIMALS PER C 0 Practicalities of using fresh tissue/stem cells PracticalitiesLack of suitable of using animal fresh tissue/stemmodels cells Lack of suitable animalPracticalities models of using fresh tissue/stem cellsLack of suitable animal models Obtaining correct ethical consent documentation ObtainingCost correct ethical consent documentation Cost Obtaining correct ethical consent documentationCost 0 Inter-individual variability Inter-individualOther variability Other Inter-individual variability Other 10 20 30 40 50

Logistical issues e.g. transport, shelf-life Logistical issues e.g. transport, shelf-life Logistical issues e.g. transport, shelf-life NUMBER OF COMPOUNDS ANALYSED

!"#$%&'(%)*&

)*+,-$+./012$,30$+.30$ NO YES 30104,-5$ "(#$ 14 13 6..3$730/89:45;$.<$,-8+,1$ '#$ +./012$ =,9>$.<$2*85,?10$,-8+,1$ 9 "&#$ 10 !"#$ +./012$ 14 13 @.25$ 16 2 17 "%#$ Inadequate supply and characterisation of tissues Human models are more relevant Human models are more relevant Human models are more relevant Perceived regulatory acceptance Poor predictivty of animal models Poor predictivty of animal models Poor predictivty of animal models A5B03$ Practicalities of using fresh tissue/stem cells Lack of suitable animal models Lack of suitable animal models Lack of suitable animal models Obtaining correct ethical consent documentation Cost Cost Cost Do you currently use As far as you are aware,Inter-individual variabilityDo you intend to use Other Other Other human tissue-based do you currently have Logistical issues e.g.human transport, tissue- shelf-lifbasede assays for safety any human tissue-based assays for safety pharmacology safety pharmacology pharmacology studies in studies? assays under evaluation the future? within your organisation?

9 10 14 13 16 2 Top 6 percieved barriers to uptake Drivers for human tissue use 17 of human tissue approaches

Do you currently use As far as you are aware, Do you intend to use human tissue-based do you currently have human tissue-based assays for safety any human tissue-based assays for safety pharmacology safety pharmacology pharmacology studies in studies? assays under evaluation the future? within your organisation?

Top 6 percieved barriers to uptake Drivers for human tissue use of human tissue approaches 12 | 13 Highlights

New method to culture hepatocytes from adult mouse stem cells awarded 3Rs Prize

The annual international NC3Rs Prize has the development of a biocompatible been awarded to Dr Meritxell Huch for a skull implant for cognition studies in publication in Nature that describes the non-human primates that significantly first successful expansion of mouse liver improves animal welfare. stem cells into 3D structures that resemble functional liver tissue. Winner

For decades scientists have attempted to Dr Meritxell Huch regenerate hepatocytes but until now no Hubrecht Institute for Developmental Biology laboratory has been successful in identifying and Stem Cell Research. Presently at The and growing such cells in culture. The mouse Gurdon Institute, University of Cambridge. has traditionally been the only method for the study of stem cells during tissue regeneration. Huch M, Dorrell C, Boj SF, van Es JH, Li VSW, van de Wetering M, Sato T, Hamer K, Sasaki Dr Huch and colleagues, from the Hubrecht N, Finegold MJ, Haft A, Vries RG, Grompe M, Institute for Developmental Biology and Stem Clevers H (2013). In vitro expansion of single + Cell Research, The Netherlands, have identified Lgr5 liver stem cells induced by Wnt-driven a marker (Lgr5+) for a particular class of stem regeneration. Nature 494: 247–252. cells that become active when the liver is damaged. Isolating these cells in a novel liver Highly commended culture system results in the infinite expansion Dr Gyorgy Fejer of long-lived mouse hepatocytes that could University of Plymouth be used for high-throughput drug screening, toxicology safety studies and research on Fejer G, Wegner MD, Györy I, Cohen I, liver regeneration, replacing the use of mice. Engelhard P, Voronov E, Manke T, Ruzsics Clinically, the application of the technology to Z, Dölken L, Prazeres da Costa O, Branzk human hepatocytes has enormous potential N, Huber M, Prasse A, Schneider R, Apte for the regeneration of damaged livers and RN, Galanos C, Freudenberg M (2013). treatments for patients with liver diseases. Nontransformed, GM-CSF–dependent macrophage lines are a unique model The £20k prize, which is sponsored by to study tissue macrophage functions. GlaxoSmithKline, is for an outstanding PNAS 110(24): E2191–E2198. contribution to scientific and technological advances in the 3Rs, published within the last three years. We received 22 applications, with Dr Daniel Adams over half from researchers outside of the UK. University of California, San Francisco

Two highly commended awards have also Adams DL, Economides JR, Jocson CM, been made for publications describing Parker JM, Horton JC (2011). A watertight an opportunity to reduce rodent use in acrylic-free titanium recording chamber for biomedical research through the development electrophysiology in behaving monkeys. of a new method to culture macrophages, and J. Neurophysiol 106: 1581–1590. Liver organoid in culture 14 | 15 Highlights

New global initiative on New partnership on the 3Rs with microsampling to influence the medical research charities company and regulatory practice

4. Microsampling (p. 13) The development of analytical methods of animals used for regulatory toxicology For many years, we have worked with the of Animals in Bioscience Research; the which allow the analysis of very small blood purposes, has yet to be realised. To address MRC, BBSRC and Wellcome Trust to ensure latter was updated and reissued in 2013 to samples (referred to as microsampling) taken this, in May, we organised a workshop to the 3Rs are fully embedded in the peer reflect changes to the UK’s animal research from rodents during toxicology studies can consider the scientific, practical and review of research proposals involving legislation. Charities will refer research eliminate the use of satellite animals for regulatory issues around microsampling. The animals. This year, we began a new strategic proposals involving the use of non-human toxicokinetic analysis as those in the main output of the workshop has been accepted partnership with the Association of Medical primates, cats, dogs and equines to the study group can be used for multiple blood for publication in Drug Discovery Today. Research Charities (AMRC) to assist more NC3Rs for 3Rs review to help ensure that sampling without compromising animal of its members in promoting the 3Rs in the all opportunities to minimise animal use welfare. In recent years microsampling We have subsequently established an research they support. In April, we held a joint and improve animal welfare are identified. has become increasingly used by many expert network with 42 members from 33 workshop for charity research management Eighty-four such reviews were performed companies in early studies such as those organisations (including pharmaceutical and policy staff to explore changes to peer for the MRC, BBSRC and Wellcome Trust in for dose range finding. Nevertheless there companies and regulatory authorities) to review processes, grant conditions and 2013, taking the total number carried out is reluctance to use it for toxicology studies provide an evidence base for the wider use policies in terms of the 3Rs, which were to date to 446. because of perceived regulatory hurdles of microsampling. This will be used to inform subsequently ratified at the AMRC annual and concerns that sampling will compromise discussions on microsampling which have general meeting in November. During 2014 we will deliver a programme key endpoints such as haematology. This recently been initiated by the ICH – the body of tailored support and resources, including means that the full reduction potential of which is responsible for the international Member charities will be joining the major a second workshop, to assist member microsampling, which could halve the number harmonisation of pharmaceutical regulations. UK research funding bodies in adopting charities in making changes to their guidelines developed by the NC3Rs, such processes and practices in advance of as ARRIVE and Responsibility in the Use an AMRC peer review audit in 2015.

Number of grant applications reviewed by the NC3Rs on behalf of the major funders

90 84 Microsampling can reduce by up to half the use of rodents in toxicity studies 80

70 OneOne mmonth Rat dosed One-montOne-m h ThrThreee-monte- h 65 rraangn e rat toxicityx rat toxxicity 60 totoxicityxicity study 60 58 UPU TOiinn a rat nd nding studstu y stustudy 50% 50 RER DUCTIONCTCTIOON 42 40

TIONS REVIEWED 39 UPUP TTOO 25% UPUP TTOO 50% UPUP TOTO 23% UPUP TOTO 50% A RREDEDUCCTION REDUCCTION REDREDUCTIONC REDUCTIONC 30 30 27 23 20 18

NUMBER OF APPLIC 10 5 2004 200 2006 2007 2008 2009 2010 2011 2012 2013

Conventional design Conventional design Conventional design 48 104 158 Micro-sampling design Micro-sampling design Micro-sampling design 24 80 80

Microsampling can reduce by up to half the use of rodents in toxicity studies. 16 | 17 Highlights AR RIVE

JOURNALS ENDORSING 14 77 176 335 ARRIVE

2010 2011 2012 2013

JOURNALS REPUBLISHED AR RIVE 11 ARRIVE 2500+ EDITORIALS POCKET GUIDES 22 ON ARRIVE SENT TO MAJOR New call to universities to FUNDERS SUPPORT support the better reporting 10 ARRIVE of animal studies UNIVERSITIES SUPPORT 22 22 ARRIVE COUNTRIES In September, we published a call for duringJOURN 2014.ALS Changing reporting practice universities to formally adopt the ARRIVE willENDORSING require a cultural shift and we are 4,000 Visits to ARRIVE page on NC3Rs website guidelines,14 which were77 developed176 by the 335 collaboratingARRIVE with a number of the journals NC3Rs to improve the reporting in the which have signed up to the guidelines to help Views of the original paper reporting ARRIVE in PLOS Biology 3,500 scientific literature of research involving embed them in their peer review processes. animals. The call was part of our wider 3,000 strategy2010 to encourage2011 uptake2012 and use of the2013 International interest in the ARRIVE guidelines guidelines by researchers, funders, journals continues to grow and we are currently in 2,500 and institutions. To date 22 universities have the process of translating the guidelines committed to incorporating the ARRIVE into Chinese and Portuguese to reflect the 2,000 guidelines into local policies and practice. growing science base within the so-called JOURNALS BRIC nations, Brazil, Russia, India and China. 1,500 During the last year, theREPUBLISHED number of journals The guidelines were re-formatted in 2013 endorsing the ARRIVEARRIVE guidelines has into a pocket-sized reference – over 2,500 1,000 increased by 90% from 176 to 335, including copies have been distributed to researchers 11 500 some of the highest impact journals. We will in 22 countries. continue to work to increase this number 2500+ 0 POCKET GUIDES -12 -12 -12 un-12 un-13 EDITORIALS Jun-10 Aug-10 Oct-10 Dec-10 Feb-11 Apr-11 Jun-11 Aug-11 Oct-11 Dec-11 Feb-12 Apr J Aug Oct Dec-12 Feb-13 Apr-13 J Aug-13 Oct-13 Dec-13 22 ON ARRIVE SENT TO MAJOR FUNDERS SUPPORT 10 ARRIVE

UNIVERSITIES SUPPORT 22 22 ARRIVE COUNTRIES

4,000 Visits to ARRIVE page on NC3Rs website Views of the original paper reporting ARRIVE in PLOS Biology 3,500

3,000

2,500

2,000

1,500

1,000

500

0

-12 -12 -12 un-12 un-13 Jun-10 Aug-10 Oct-10 Dec-10 Feb-11 Apr-11 Jun-11 Aug-11 Oct-11 Dec-11 Feb-12 Apr J Aug Oct Dec-12 Feb-13 Apr-13 J Aug-13 Oct-13 Dec-13 18 | 19 Highlights

2013 at a glance

September May November January NC3Rs media briefing Publication in in partnership with the Launch of a new New tutorial on aseptic Regulatory Toxicology Science Media Centre network for Named surgery in rodents March and Pharmacology July at the annual British Animal Care and launched on the NC3Rs- on reducing animal Science Festival. Welfare Officers sponsored Procedures First meeting of the new Professor Stephen use in pharmaceutical working with non- with Care website. NC3Rs expert working Holgate CBE, University toxicology. human primates, group on applying the of Southampton, to complement the 3Rs to mammalian appointed as the NC3Rs annual Primate 01 models of epilepsy. 05 NC3Rs Board Chair. 09 Welfare Meeting. 03 07 11

April August December February October NC3Rs blog launched. June Co-hosted conference 14 new PhD Winner announced in Newcastle on the Joint workshop on studentships awarded, for the first CRACK Two David Sainsbury euthanasia of rodents novel non-mammalian totalling £1.26 million. IT Mini-Challenge fellowships awarded, and fish. approaches to study competition for the totalling £390k. development of severe asthma held a device to refine with the British intravitreal injections Thoracic Society in rabbits. Difficult Asthma 04 Network. 12 02 06 08 10

Annexes 20 |21 Annexes Acronyms NC3Rs funders Financial summary NC3Rs staff NC3Rs Board members CRACK ITSolutions CRACK ITChallenges Infrastructure for Impactgrants Pilot study grants Project grants David SainsburyFellowships PhD Studentships NC3Rs events 3 22 | 23 Annex

NC3Rs events

In 2013, we held 16 events attended Symposium: Newcastle consensus meeting Workshop: Primate neuroimaging: by around 1,400 delegates. A list of on laboratory animal euthanasia tools for animal welfare and science the events is provided below. 9 August 4 November Co-organised with Newcastle University Co-organised with the University of Oxford to establish a consensus view on the and Newcastle University with funding humaneness of various euthanasia from the Wellcome Trust to showcase 3Rs techniques for rodents and fish. advances in imaging technologies and their application in non-human primates. Workshop: Launch of the CRACK IT 2013 Challenges Workshop: NACWO Networking Symposium: NC3Rs science review Workshop: Overcoming the barriers for 5 September 5 November 26 February uptake of microsampling techniques in Formal launch of the 2013 competition, Informal meeting to bring together regulatory toxicology Annual event providing a scientific review including networking opportunities for NACWOs working with non-human 18 June of the NC3Rs programmes, research funding potential applicants with industry sponsors. primates to forge a supportive network and future plans. Joint event with the ESP KTN to showcase and share new practices and ideas. the latest advances in preclinical imaging Workshop: De-bunking the urban myth: Symposium: Applying mathematics technologies and their application from a rodents don’t support biotech programs Symposium: Launch of the 2013 to 3Rs problems 3Rs perspective. 8 – 11 September Research Review 15 – 18 April 20 November In collaboration with Charles River Symposium: NC3Rs/Society of Biology Joint event with the EPSRC-funded Laboratories, USA, a workshop on species Launch of the second Research 3Rs annual event Mathematics in Medicine Study Group to selection based on weight of evidence Review publication showcasing 19 June connect mathematicians and biologists gathered from pathway and drug actions, NC3Rs-funded science. with the aim of solving problems which if Joint event with the Society of Biology to rather than generalised regulatory guidance. addressed could replace or reduce the use showcase scientific advances which improve of animals. the utility and efficiency of animal models, Workshop: A pathways approach to Workshops: Non-animal technologies reduce reliance on in vivo research through reducing animal use in severe asthma consortia building workshops Workshop: How can charities support the use of new technologies and approaches, research 10 and 12 December the 3Rs in animal research? 14 October and maximise laboratory animal welfare. Two consortia-building workshops 24 April Joint event with the British Thoracic Society held in Manchester and London in Workshop: Non-animal technologies Joint event with the AMRC to explore how Difficult Asthma Network to consider the collaboration with the TSB to support 25 July and 21 August medical research charities can use peer potential for developing pathways-based the new funding competition for feasibility review to ensure the highest standards Two workshops held in collaboration with approaches to severe asthma using human studies on the commercialisation of non- and implementation of the 3Rs in the the TSB to establish the readiness of new tissue and non-mammalian species. animal technologies. research they support. technologies to be commercialised to replace animal use. 24 | 25 Annex

NC3Rs awards David Sainsbury

In 2013 we made a total of 54 awards through our various Fellowships funding competitions. These are listed by scheme.

Professor Chris Secombes Awards were £195k Scheme Amount awarded University of Aberdeen over three years Project grants £1,670,259 Development of a method for non-lethal Pilot study grants £666,939 sampling from individual fish to investigate Dr Maria Eugenia Herva Moyano host responses to ectoparasites PhD Studentships £1,260,000 University of Cambridge Dr Sridhar Vasudevan Development of a sensitive in vitro system David Sainsbury Fellowships £390,000 University of Oxford for anti-alpha-synuclein aggregation drug Infrastructure for Impact grants £1,315,253 Development of a patient-derived cellular screening CRACK IT Challenges £2,958,248 model of circadian disruption in bipolar Ms Juliane Liepe disorder Imperial College London Total £8,260,699 Dr Marc Veldhoen Signalling pathways of leukocyte migration Babraham Institute in silico Towards engineering a multi-cell lineage multi-organism intestine PhD Studentships Dr Grant Wheeler University of East Anglia Development of a non-mammalian, preclinical Awards were £90k Professor Catherina Becker screening tool (FETOX) for predictive Analysis over three years University of Edinburgh of Drug Safety. Motor neuron regeneration in larval zebrafish Professor Robin Williams Dr Darragh Murnane Dr Andrew Dilley Royal Holloway, University of London University of Hertfordshire University of Sussex Find the target of valproic acid; pioneering DM-MAP: Drug and Metabolite Microsampling Development of a refined model of the use of a non-animal model for basic Analytical Platform for preclinical medicines neuropathic pain: a model without frank nerve biomedical (epilepsy) research development injury Professor Colin Willoughby Dr J. Arjuna Ratnayaka Professor Liam Grover University of Liverpool University of Southampton University of Birmingham Developing molecular therapies for glaucoma Exploitation of an ex vivo disease model Creating an in vitro model of pathogenic using an ex vivo human organ culture system to characterise early events in retinal ossification to explore methods for dispersion Dr Michele Zagnoni degeneration Dr Rachel Lawrence University of Strathclyde Professor Margaret MacLean Royal Veterinary College Developing microfluidic systems for high- University of Glasgow Replacing rodent models for investigating throughput studies of functional neuronal An in vitro model to investigate the role of the influence of the microbiome upon innate networks oestrogen and oestrogen metabolism in immune responses and resistance pulmonary vascular disease to pathogens 26 | 27 Annex

Project grants Pilot study grants Infrastructure for Impact grants

Dr Robert Davies Professor Catherina Becker Dr Gyorgy Fejer Professor Paul Flecknell University of Glasgow University of Edinburgh University of Plymouth Newcastle University A 3D air-liquid interface airway epithelial cell Finding effective analgesics in zebrafish by Establishment of non-transformed, Training and teaching resources to underpin model to study pathogen interactions within analysing effects on the nervous system continuously growing, alternatively activated implementation of refinement of in vivo the bovine respiratory tract (£390,050) (£73,770) mouse macrophage cell lines (£75,492) studies (£64,556)

Dr Manolis Fanto Dr Emily Bethell Dr Samuel Solomon Professor Malcolm Macleod King’s College London Liverpool John Moores University University College London University of Edinburgh Drosophila as a model to understand the role Attention Bias: A novel method to assess Reducing the number of non-human primates ivSyRMAF- the CAMRADES- NC3Rs in vivo of glial cells in neurodegeneration (£316,462) psychological well-being in group-housed in research by developing a rodent model of systematic review and meta-analysis facility non-human primates (£74,114) selective attention (£72,593) (£504,931) Dr Julius Hafalla London School of Hygiene and Tropical Dr Bertrand Collet Dr Liku Tezera Dr John Marshall Medicine Marine Scotland Science University of Southampton Queen Mary, University of London 3Rs of murine models of malaria infection: Novel approaches to immortalise salmon fish Investigating tuberculosis by engineering Multi-user, multi-centre MRI to reduce and immunology meets experimental genetics cells (£74,443) human granulomas (£74,450) refine the use of mice in cancer and trauma (£317,995) research (£250,000) Dr Andrew Devitt Dr David Weinkove Professor Ian MacKenzie Aston University Durham University Professor Valerie Speirs Queen Mary, University of London University of Leeds Towards an in vitro system of predictive Using C. elegans to produce proteins from Replacement of murine transplantation biomarkers of in vivo liposome efficacy parasitic nematodes for research and SEARCHbreast: A virtual resource to assays by 3D in vitro substitutes for the (£74,494) therapeutic use (£74,223) facilitate sharing breast cancer materials and assessment of therapeutic responses of knowledge to benefit the 3Rs (£495,766) cancer stem cells (£344,331) Dr Julia Edgar University of Glasgow Professor Maria Grazia Spillantini Development of an in vitro screening University of Cambridge system to minimise animal use in the search Applying the 3Rs to elucidate the for factors that modulate (re)myelination mechanisms of tau pathology using DRG (£73,355) neurons in culture (£301,421) 28 | 29 Annex

CRACK IT CRACK IT CRACK IT Challenges 2012 Challenges 2013 Solutions 2013 – Phase 2 awards – Phase 1 awards

Rodent Little Brother UnTangle Dr Josephine Bunch Professor Robin Williams National Physical Laboratory Royal Holloway, University of London Professor Douglas Armstrong Dr Eric Hill £99,985 £30,000 Actual Analytics Aston University £500,000 £95,453 Dr Victoria Hutter Developing an ethical, fast, and inexpensive University of Hertfordshire early-indicator screen for taste aversive and Professor Maria Grazia Spillantini ProBE IT £55,050 emetic effects of novel chemical entities University of Cambridge No funding awarded for this Challenge £66,898 Dr Tamer Mohamed NephroTube University of Manchester Dr Selina Wray DRGNET £30,000 University College London Dr Colin Brown Six month extension for both teams. Phase 2 £99,956 Newcastle University Novel and reliable method to screen for drug funding will be decided in May 2014. £99,726 Dr Christopher Ward cardiac toxicity using human pluripotent stem cell derived cardiomyocytes (hPS-CM) University of Manchester Dr Paul Jennings PreDART £81,956 Innsbruck Medical University Dr Alex Easton £99,330 Durham University Professor Raymond Pieters £29,850 Institute for Risk Assessment InPulse Dr Roisin Owens Sciences/Toxicology Ecole Nationale Superieure Reducing animal numbers in tasks of memory Professor Chris Denning £750,000 des Mines de St Etienne University of Nottingham £100,000 Dr Dan Daly £100,000 Lein Applied Diagnostics Mini Challenge Dr Martijn Wilmer Dr Cesare Terracciano £30,000 Radboud University Medical Centre Imperial College London Real Time Confocal Tracking of Ultrasound RETINAS £99,958 £99,323 Mediated Drug Delivery

Mr Allen Pearson Professor Wolfram Zimmermann Dr Dave Hay Origin Product Design University Medical Center Göttingen Virtual Infectious Disease FibromEd Products Limited £50,000 £100,000 Research £30,000 Professor Tom Freeman Inhalation Translation The Roslin Institute, University of Edinburgh Using physiological levels of fluid shear stress £84,561 to improve hepatocyte function Professor Mark Bradley University of Edinburgh Professor Paul Kaye £98,639 University of York £100,000 Dr Ben Forbes King’s College London £81,041 30 | 31 Annex

NC3Rs Board members NC3Rs staff

Professor Stephen Holgate CBE (Chair) Dr Vicky Robinson Dr Virginie Bros Facer (from July 2013) Chief Executive (from August 2013, maternity leave cover) University of Southampton Programme Manager, Research Funding Innovation and Translation Group Professor Jamie Davies (Deputy Chair) Dr Katie Lidster Dr Kathryn Chapman University of Edinburgh (from February 2013) Head of Innovation and Translation Science Manager Dr Phil Botham Syngenta Dr Joanna Edwards Miss Suzanne McArdle (from March 2013) (from April 2013) Professor Margaret Dallman Science Manager Research Funding Officer Imperial College London Dr Anthony Holmes Mrs Hazel McLaughlin Dr Lesley Heppell Programme Manager, Technology Research Funding Administrator BBSRC Development Dr Nathalie Percie du Sert Professor Ian Kimber OBE Mr David McCreanor Programme Manager, Experimental Design (Chair until July 2013, member from July 2013) (from April 2013) University of Manchester CRACK IT Administrator Mr Dan Richards-Doran Communications Manager Dr Tony Peatfield Ms Colette Roach MRC (from December 2013) CRACK IT Officer Miss Emma Stokes Dr Ian Ragan Website and Design Manager Independent Dr Fiona Sewell Programme Manager, Toxicology and Business Support Group Dr Vicky Robinson Regulatory Sciences (Human Health) NC3Rs Miss Maureen FitzGerald Events Administrator Dr Cathy Vickers Dr Malcolm Skingle CBE (from January 2013) (until July 2013) Miss Joanne James Programme Manager, CRACK IT GlaxoSmithKline (from February 2013) Events Officer Dr Carl Westmoreland Research Management and Communications Group (from October 2013) Mr Jonathan Lind Unilever Dr Mark Prescott Office Administrator Head of Research Management and Mr Neil Yates Ms Ashley Scott University of Nottingham Communications Business Manager Dr Rubina Ahmed (on maternity leave from July 2013) Ms Caroline Shriver Programme Manager, Research Funding (from September 2013) Strategic Planning Manager 32 | 33 Annex

Financial summary

This annual report describes the NC3Rs activities for the calendar year Income 2012/13 2011/12 2013. The financial accounting period runs from 1 April to 31 March £ million £ million each year. The UK Shared Business Services Ltd (UK SBS) provides the Government1 11.79 5.46 NC3Rs with accounting and budget management services with additional Charity 0.12 0.11 support from the MRC. The financial information provided covers the Industry 0.13 0.14 period 1 April 2012 to 31 March 2013 and has been compiled using data Total 12.04 5.71 from UK SBS. The annual budget is agreed by the NC3Rs Board.

Expenditure 2012/13 2011/12 Income Expenditure £ million £ million Programme Total income for this financial period Total expenditure increased from £6.47 million 1.06 1.11 costs was £12.04 million, which includes in 2011/12 to £12.03 million in 2012/13. This is £3.6 million of deferred income from due to the planned spend of deferred income Operating 0.42 0.40 previous financial years. from previous financial years through the costs increased awards committed via the NC3Rs Awards costs 10.54 4.96 The income from ‘Government’ comes research funding schemes. Awards typically Total 12.02 6.47 from the Department for Business, commit expenditure over a three year period Innovation and Skills (via the Research with payments spread over four financial Councils and the TSB), the Home Office years so award costs in 2012/13 relate to and Defra. In 2012/13 there was a 27% funding awarded between 2008 and 2012. increase in funding from the MRC and a Financial Commitments Spend 26% increase in funding from the BBSRC. Programme costs cover science initiatives year made on on awards led by the NC3Rs staff and include staff new awards £ million salaries and costs for working groups, £ million workshops and events. In the period 2012/13, expenditure on programme 2009/10 4.86 1.86 costs was £1.06 million. 2010/11 6.13 3.93 2011/12 9.18 4.96 Operating costs include staff salaries for core administrative duties, staff travel and 2012/13 8.76 10.54 training, recruitment, stationery, rental and service charges and publishing costs. In the

period 2012/13, expenditure on operating 1 £3.6 million deferred income from previous financial years. costs was £0.42 million. Government contribution in 2012/13 totalled £8.19 million. 34 | 35 Annex

NC3Rs funders Acronyms

The NC3Rs receives funding from the public, 3Rs Replacement, reduction and refinement of animals in research commercial and charitable sectors. A list of funders is provided below. ABPI Association of the British Pharmaceutical Industry

Association of the British Pharmaceutical Industry2 AMRC Association of Medical Research Charities Biotechnology and Biological Sciences Research Council BBSRC Department for Environment, Food and Rural Affairs Biotechnology and Biological Sciences Research Council Engineering and Physical Sciences Research Council EPSRC GlaxoSmithKline Engineering and Physical Sciences Research Council

Home Office ESP KTN Medical Research Council Electronics, Sensors and Photonics Knowledge Transfer Network SC Johnson ICH International Conference on Harmonisation of Technical Requirements Shell for Registration of Pharmaceuticals for Human Use Syngenta MHRA Technology Strategy Board Medicines and Healthcare products Regulatory Agency The Dow Chemical Company MRC Medical Research Council Unilever Wellcome Trust NACWO Named Animal Care and Welfare Officer

SME Small and Medium-sized Enterprises

TSB Technology Strategy Board

2 In accordance with the Association of the British Pharmaceutical Image credits Industry’s (ABPI) Code of Practice regulating the pharmaceutical Page 9: UCL Centre for Advanced Biomedical Imaging industry, the following companies have provided funding to Page 13: Hubrecht Institute for Developmental Biology the NC3Rs as part of the ABPI-NC3Rs collaboration: ABPI, and Stem Cell Research AstraZeneca plc., Covance Laboratories Ltd., GlaxoSmithKline plc., Huntingdon Life Sciences Ltd., Eli-Lily and Company Ltd., Pfizer Ltd., and Novartis Ltd. 2013

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T +44 (0)20 7611 2233 F +44 (0)20 7611 2260 [email protected] Annual Report twitter: @nc3rs The material used in this publication is derived from sustainable and renewable sources. The Paper is FSC® and ISO14001 accredited. www.nc3rs.org.uk All inks used are vegetable based and all www.crackit.org.uk pulp is Elemental Chlorine free (ECF) Pioneering Better Science