The case for model-driven research Hans Lerach, Brain new... · Gaspard et al.,2008 Intrinsic +...

• current research paradigm - identifies biological mechanisms with simple causality

• evolution generates a ‚dark mass‘ of mechanisms not accessible to current research tools.

• Mechanistic models - compare experimental results and prediction to falsify hypothesis too complex to analyse by currently available strategies

The case for model-driven research

Cancer pathways include:

RTK signaling HEDGEHOGNOTCHWNTTGFB signaling Cytokine signaling Death receptor signaling GCPR/Hormone signaling Ephrin signaling

• 50 signalling pathways

• 20,000 reactions

• 800 genes

• 300 targeted drugs

Wierling et al., 2015

PMID:26464088

ModCell™ - a generic mechanistic model of cellular signalling transduction

www.alacris.de

Human signalling pathways

www.alacris.de

We need samples for molecular analyses

Fresh human samples

Deep brain stimulation-associated brain tissue imprints: a new in vivo approach to biological research in human Parkinsons disease

Affif Zaccaria, Ali Bouamrani, Stephan Chabardès, Michèle El Atifi, Eric Seigneuret, Johannes A. Lobrinus, Michel Dubois-Dauphin and Pierre R. Burkhard

Watanabe et al.,2005

Dkk-1 ; Lefty-1

Elkabetz et al., 2008

NogChambers et al.,2009

SB431542; Nog

Gaspard et al.,2008

Intrinsic + Cyclop. Dkk-1; Lefty-1

Eiraku et al., 2008 Shi et al., 2012

DM/Nog; SB431542

FGF2Dkk-1; 1BMPRIA-Fc

SB431542

Mariani et al., 2012

Pasca et al., 2013

DM; SB431542

Lancaster et al., 2013

Intrinsic

Kadoshima, 2013

IWRe; SB431542

Edri et al., 2015

Nog; LDN; SB431542

Qian et al., 2016

Surrogate brain tissue:Diverse Methods to Generate Brain Organoids

Qi et al., 2017

LDN; SB431542; FGF-i

Bershteyn, 2017

SB; IWReIntrinsic (CHIR)

Lancaster et al., 2017

XAV; LDN; SB431542;

Purmorphamine

Maroof et al., 2013

Human genome project1 human genome/ 13 years

GAII: Hiseq machines1 human genome/few days

Novaseq6000 60 genomes in parallel

1990-20002006-2012

One NGS run generates as much information as one million runs on the sequencers used 10 years ago

Genomics dominates “omics”

Resolving RNAseq data spatially at the protein level by Imaging Mass Cytometry (IMC)40 Ab in one experiment

M.-L. Yaspo, Unpublished

CRISPR variants

Martin Kampmann, Trends in Molecular Medicine, June 2017, Vol. 23, No. 6, 483-485

CRISPR-phenotype screens

Martin Kampmann, Trends in Molecular Medicine, June 2017, Vol. 23, No. 6, 483-485

CrispR Droplet sequencing: CROPseq (Christoph Bock)

Hill et al., Nature Methods, Feb. 2018

Lineage tracing: EvolvR

Halperin et al., Nature 560 (2018)248-252

"Brain, New Approach to Brain Diseases” Workshop 21st November 2018

Brain network dynamics simulations

Schirner, Rothmeier, Jirsa, McIntosh, Ritter 2015 Neuroimage An automated pipelinefor constructing personalized virtual brains from multimodal neuroimaging data

Inferring unobservable mechanismsthrough personalized simulation

Schirner, McIntosh, Jirsa, Deco, Ritter 2018 eLifeInferring multi-scale mechanisms using brain network modelling

Liniking systems biology andcomputational neuroscience

Iyappan et al. 2016 J Alzheimer’s Disease. Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration

Applications in Stroke, Epilepsy, Tumors, Dementia, Schizophrenia...

E.g. Proix et al. 2017 Brain ; Jirsa et al. 2014 Brain; Zimmermann et al. 2018 Neuroimage Clinical; Aerts et al. eNeuro 2018

100 000 virtual brains from uk biobank

Examples

• Parkinson‘s disease: models based on –omicsanalysis of cells recovered during therapeutic deepbrain stimulation

• MS: deep immune status, modelling the immune system, analysis of monocygotic twins with/withoutMS

• Migraine: GWAS modelling, brain simulation (Petra Ritter, Charité)

• ......

FET-Flagship project applicationwww.digitwins.org

Without DigiTwins (www.digitwins.org), we will, over the next framework program

• Spend €10 trillion on healthcare

• Spend ~€2 trillion on drugs, to which the individual patients do not respond, and their consequences

• Have the equivalent of the population of Milan die of adverse drugreaction

• Come 7 years closer to the implosion of the European healthcaresystem

• Make little progress on biological mechanism with complex causality

• Save €1 bn over 10 years, the equivalent of the amount we spend in healthcare every 5 hours (and probably waste every 10 hours).

If you think this could be relevant to Europe and the European Citizens, please mail (lehrach@molgen.mpg.de) or call (+491723839194) me (andtell your colleagues).

The case for model-driven research Hans Lerach, Brain new... · Gaspard et al.,2008 Intrinsic +...

Documents

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