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The European Commission’s scienceand knowledge service
Joint Research Centre
The need to improve human relevance in biomedical research
Francesca PistollatoDirectorate F – Health, Consumers and Reference MaterialsChemical Safety and Alternative Methods Unit (F3) incorporating EURL ECVAM
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Directive 2010/63/EU on the protection of animals used for scientific purposes
➢Stimulate development
➢Coordinate validation
➢Provide information
➢Promote dialogue
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Non-communicable chronic diseases Some facts:
➢ increasingly prevalent in Western countries
➢ > 86% of total premature deaths
➢ result of a combination of genetic, physiological, and environmental factors (e.g., diet, exercise and smoking)
➢ basic/fundamental and pre-clinical research successes using animals have not, in most cases, translated into effective therapeutic treatments for humans
➢Alzheimer: 244 drugs in 413 trials (2002-2012) → failure rate 99.6%!
(Cummings et al., Alzheimers Res Ther 2014 6, 37)
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https://www.ft.com/content/c4e1241e-f731-11e7-88f7-5465a6ce1a00
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Time to question some hypotheses:
correlation vs adaptation vs causation?
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Are we looking at the right models?
Mellor B. Nature 2008
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Animal models of Alzheimer’s disease
AD research → animal models (Tg & inbred mice) → to recapitulate genetic & pathological traits of human AD
Tg animals:
✓ Aβ formation
✓ neuritic plaques
✓ NFTs
✓ Gliosis
✓ Synaptic alterations
✓ Some signs of cognitive impairment
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Tg animals:
NO clinico-pathological complexity of AD
Translational research failure
Generate false negative data →
exclusion of potentially effective compounds from clinical studies
Animal models of Alzheimer’s disease
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(ALTEX. 2014;31(3):279-302.)
Animal models of Alzheimer’s disease
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<5%
>95%
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→ bias in the peer-review process ?
http://projectreporter.nih.gov/reporter.cfm
Funding for AD research
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A new roadmap for biomedical research ?
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reductionist holistic
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How can we tackle these issues?
New priorities
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Can we learn from the transition in toxicology?The need to improve human relevance
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The ‘adverse outcome pathway’ (AOP) concept
in biomedical research
➢ What signaling pathways get perturbed at the onset of the disease?
➢ Can we link environmental & genetic causes with whole-person outcomes, via multiscale AOPs?
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ORGANISM /
BODY
ORGAN / TISSUE
CELLPROTEIN / SIGNALING PATHWAY
EPIGENETIC / GENETIC
POPULATION
What are the tools & models available to cover the different levels of biological
complexity ?
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Observational, epidemiological, intervention studies on humans (e.g., Phase 0, microdosing)
ORGANISM /
BODY
ORGAN / TISSUE
CELLPROTEIN / SIGNALING PATHWAY
EPIGENETIC / GENETIC
POPULATION
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ORGANISM /
BODY
ORGAN / TISSUE
CELLPROTEIN / SIGNALING PATHWAY
EPIGENETIC / GENETIC
POPULATION
Human ex vivo tissue (healthy & diseased, e.g. brain, CSF, blood)
Imaging: MRI, PET, connectomics
Cognitive tests: MMSE, HVLT
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ORGANISM /
BODY
ORGAN / TISSUE
CELLPROTEIN / SIGNALING PATHWAY
EPIGENETIC / GENETIC
POPULATION
Human induced pluripotent stem cells (hiPSCs) & neuronal derivatives (normal & patient)
(A. Muotri, www.ucsd.edu)
3D cell models: improved viability, cellular & tissue properties retained in vitro
Nature. 2013 Sep 19;501(7467):373-9.
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ORGANISM /
BODY
ORGAN / TISSUE
CELLPROTEIN / SIGNALING PATHWAY
EPIGENETIC / GENETIC
POPULATION
Microfluidics, organ-on-chip:Rapid, reproducible, sensitive
…available also in high-throughput format for drug testing…
mimetas.com
wyss.harvard.edu/
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ORGANISM /
BODY
ORGAN / TISSUE
CELLPROTEIN / SIGNALING PATHWAY
EPIGENETIC / GENETIC
POPULATION
Next-generation sequencing (‘omics’)
Integrated computer modeling
Systems biology & pharmacology
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✓ disease pathways (onset & progression)
✓ drug targets, efficacy & toxicity
✓ Human-relevant information earlier in drug development
✓ Possible reduction of late-stage drug attrition
✓ multi-scale data integration:e.g., Omics data ↔ patients’ cognitive scores ↔ neuroimaging
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Technical challenges
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Regulatory approach
Knowledge challenges
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(Pistollato F et al. Oncotarget. 2016 Jun 28;7(26):38999-39016.)
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Some possible recommendations
✓ Implement funding for the production and centralized distribution of patient-derived cells (e.g. iPSCs)
✓ Allocate funding on centres conducting omics research in human-based settings
✓ Foster the design of preventive strategies (e.g., definition of early biomarkers of human diseases for early diagnosis)
✓ Encourage the creation of ‘pathways to disease’ framework(s), following the AOP approach
✓ Allocate funding on projects focused on integrated multi-disciplinary approaches, covering multiple levels of biological complexity
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3 upcoming book launch events:
Baltimore, MD at Johns Hopkins University (November 30, 2018)
London, UK (March 3, 2019)
Munich, Germany (June 14-15, 2019)
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some of our recent activities…
3Rs
and beyond…
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EP Pilot project at EURL ECVAM
Support to the development of a 3Rs education and training strategy with accompanying guidance, and the development of practical 3Rs education and
training resources
Support in the development of specifications for 3Rsguidance documents for education decision makers
Set of practical teaching resources on alternative approaches tailor-made to support learning for:
➢ high school students➢ university students➢ early-career scientists
Study kick-off in September 2018© flaticon.com
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Review of 3Rs education and training resources
• Overview of existing education and training opportunities worldwide in the area of 3Rso course format
o target audience (high school, university and professional levels)
o details on learning outcomes, topics and methodology
• Review carried out combining targeted searchand survey (June- July 2018)
Provide a valuable snapshot view to use as inventory tool and to help identify opportunities for targeted initiatives in 3Rs education and training
Ongoing study till end of 2018
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Feasibility study on indicators of alternative methods or approaches to animal experimentation
Measuring and monitoring the level of development and uptake of non
animal methods in basic/applied research, educational and regulatory context
Ongoing study till end of 2018
➢ Highlights trends➢ Drive new opportunities
for research and future funding
➢ Inform and support policies
Preliminary distribution of identified indicators
in categories
Identification
Characterisation
Pilotdemonstration
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Review of Non-animal Methods in Use
for Biomedical Research
Collection of non-animal methods in use in basic and applied research on selected human disease areas
• Development status and applications of innovative and alternative methods (in vitro and in silico approaches)
• Extensive reviews of scientific literature and
related information sources EURL
Neurodegenerative diseases
Respiratory tract diseases
Criteria for selection of diseases
❖ Incidence/prevalence of human diseases❖ Use of animal models for mechanisms'
investigation and drug discovery❖ Potential causal link between
exposure/disease development
Ongoing study till mid 2019
Study outcomes will
➢ contribute to the uptake, implementation and promotion of non- animal methods/approaches in biomedical sciences
➢ broaden the knowledge on advances in novel non-animal methods development, providing mechanistic information and modelling human-relevant specific processes or tissues
http
s://ww
w.p
hrei.o
rg/
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Review of Non-animal Methods in Use for Biomedical Research –
NEW call
Launched(closure end October)
Breast cancer
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BridgE Across Methods in bioSciences (BEAMS)
New EURL ECVAM initiative that aims to support greater connectivity between biosciences• Emerging of new innovative technologies and
their associated methods and techniques require high levels of specialisation and expertise
• Demand for greater knowledge sharing, co-operation and interdisciplinary
Workshop, at JRC Ispra, 21-22 June 2018representatives of key organisations in the biosciences
❖ Need for common language (need for translatability across research cultures or bridgeability across methods)
❖ Iterative process of co-creation, -production, -formulation and -definition
❖ Timeliness (ensuring trust and understanding across research methods and actors, not in a post hoc manner)
http://clipground.com/
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JRC Summer School on Alternative Approaches for Risk Assessment (May 2017)
JRC Mission
As the science and knowledge service
of the European Commission,
the Joint Research Centre’s mission is
to support EU policies with independent
evidence throughout the whole
policy cycle.
The European Commission’s
science and knowledge service
Joint Research Centre
JRC Summer School 2019:
Non-Animal Approaches in Science Challenges & Future Directions
JRC Ispra
21-24 May
2019
@EU_ScienceHub
#ECVAM
Draft Agenda
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Biomedical Research 2.0
Apart from 3R concept, we should start recognizing the need to go even beyond the 3Rs, and embrace a fresh new perspective, considering the role of 'human-relevant' approaches to reply to real societal needs
Recently started project….
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Why? Despite increasing funding, two decades of research on non-communicable diseases (NDDs, metabolic syndrome, cancer, autoimmune diseases, etc.) are not yielding proportional impactful results at the societal level.One of the reasons underlying this failure is also associated with the overreliance on the use of non-human relevant models (animals) and (reductionist) approaches.
What?Incentivise innovative, human relevant approaches to reply to biomedical questions
Prioritize cutting edge projects that use human-relevant strategies to:
✓Increase public health
✓Have an economic impact
✓Reduce the number of animals used in biomedical research (the most representative area of animal use)
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GoalRe-envision biomedical research approaches and funding priorities to improve human relevance and have societal
impact
How?definition of indicators to retrospectively measure 'return on investment' of EU funded projects in order to understand:➢Possible breakthroughs provided by funded research activities that could have societal
impact (e.g., discovery of a new disease-related pathways or modes of action, improvement of diagnosis, improvement (or design of) new therapeutic strategies (or treatments), and similar aspects along this line…);
➢Whether such breakthroughs were obtained through purely in vivo, in vitro, in silico, non-invasive technologies, others, or combination of different approaches;
➢Contribution of funded research to the 3Rs
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Chemicals Safety &
Alternative Methods
+
EURL
ECVAM
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ec.europa.eu/jrc
@EU_ScienceHub
EU Science Hub - Joint Research Centre
Joint Research Centre
EU Science Hub
Thanks for your attention!