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

Directive 2010/63/EU on the protection of animals used for scientific purposes

➢Stimulate development

➢Coordinate validation

➢Provide information

➢Promote dialogue

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)

https://www.ft.com/content/c4e1241e-f731-11e7-88f7-5465a6ce1a00

Time to question some hypotheses:

correlation vs adaptation vs causation?

Are we looking at the right models?

Mellor B. Nature 2008

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

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

(ALTEX. 2014;31(3):279-302.)

Animal models of Alzheimer’s disease

<5%

>95%

→ bias in the peer-review process ?

http://projectreporter.nih.gov/reporter.cfm

Funding for AD research

A new roadmap for biomedical research ?

reductionist holistic

How can we tackle these issues?

New priorities

Can we learn from the transition in toxicology?The need to improve human relevance

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?

ORGANISM /

BODY

ORGAN / TISSUE

CELLPROTEIN / SIGNALING PATHWAY

EPIGENETIC / GENETIC

POPULATION

What are the tools & models available to cover the different levels of biological

complexity ?

Observational, epidemiological, intervention studies on humans (e.g., Phase 0, microdosing)

ORGANISM /

BODY

ORGAN / TISSUE

CELLPROTEIN / SIGNALING PATHWAY

EPIGENETIC / GENETIC

POPULATION

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

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.

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/

ORGANISM /

BODY

ORGAN / TISSUE

CELLPROTEIN / SIGNALING PATHWAY

EPIGENETIC / GENETIC

POPULATION

Next-generation sequencing (‘omics’)

Integrated computer modeling

Systems biology & pharmacology

✓ 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

Technical challenges

Regulatory approach

Knowledge challenges

(Pistollato F et al. Oncotarget. 2016 Jun 28;7(26):38999-39016.)

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

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)

some of our recent activities…

3Rs

and beyond…

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

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

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

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/

Review of Non-animal Methods in Use for Biomedical Research –

NEW call

Launched(closure end October)

Breast cancer

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/

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

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….

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)

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

Chemicals Safety &

Alternative Methods

+

EURL

ECVAM

ec.europa.eu/jrc

@EU_ScienceHub

EU Science Hub - Joint Research Centre

Joint Research Centre

EU Science Hub

Thanks for your attention!