systems biology - understanding biology at the systems level

Lars Juhl Jensen

Systems biologyUnderstanding biology at the systems level

traditional biology

can a biologist fix a radio?

Lazebnik, Biochemistry, 2004

one gene

one postdoc

all aspects

knockout phenotype

Lazebnik, Biochemistry, 2004

one gene

high-throughput biology

one technology

one lab

all genes

one aspect

systems biology

complete systems

all aspects

all genes

systems-level properties

two subfields

mathematical modeling

small systems

data integration

large systems

the system

mitotic cell cycle

grow and divide

one cell

two cells

four phases

G1 phase

growth

S phase

DNA replication

G2 phase

growth

M phase

cell division

regulation

gene expression

phosphorylation

targeted degradation

protein interactions

cell cycle modeling

core cell cycle

Chen, Mol. Biol. Cell, 2004

many equations

Chen, Mol. Biol. Cell, 2004

simulation

Chen, Mol. Biol. Cell, 2004

many parameters

Chen, Mol. Biol. Cell, 2004

requires detailed knowledge

cell cycle analysis

gene expression

cell cultures

synchronization

microarrays

time courses

Gauthier et al., Nucleic Acids Research, 2007

cycling genes

time of peak expression

exercise 1

http://cyclebase.org

S. cerevisiae

RNR1, RNR2, RNR3, RNR4

S. pombe

cdc22, suc22

which genes cycle?

do time courses agree?

do orthologs agree?

do paralogs agree?

protein networks

guilt by association

STRING

>1100 genomes

genomic context

gene fusion

Korbel et al., Nature Biotechnology, 2004

conserved neighborhood

Korbel et al., Nature Biotechnology, 2004

phylogenetic profiles

Korbel et al., Nature Biotechnology, 2004

protein interactions

Jensen & Bork, Science, 2008

genetic interactions

Beyer et al., Nature Reviews Genetics, 2007

gene coexpression

curated knowledge

Letunic & Bork, Trends in Biochemical Sciences, 2008

>10 km

text mining

Pafilis, O’Donoghue, Jensen et al., Nature Biotechnology, 2009

co-mentioning

NLPNatural Language Processing

different sources

Ensembl

RefSeq

BINDBiomolecular Interaction Network Database

BioGRIDGeneral Repository for Interaction Datasets

DIPDatabase of Interacting Proteins

IntAct

MINTMolecular Interactions Database

HPRDHuman Protein Reference Database

PDBProtein Data Bank

GEOGene Expression Omnibus

MIPSMunich Information center

for Protein Sequences

Gene Ontology

BioCyc

KEGGKyoto Encyclopedia of Genes and Genomes

PIDNCI-Nature Pathway Interaction Database

Reactome

different formats

different names

CDC2

CDK1

P06493

not comparable

variable quality

confidence scores

calibrate to gold standard

von Mering et al., Nucleic Acids Research, 2005

transfer by orthology

von Mering et al., Nucleic Acids Research, 2005

combine scores

exercise 2

http://string-db.org

Szklarczyk, Franceschini et al., Nucleic Acids Research, 2011

changing parameters

high confidence only

experiments only

evidence viewers

which interact functionally?

which interact physically?

complex regulation

time of peak expression

protein interactions

temporal network

de Lichtenberg, Jensen et al., Science, 2005

dynamic vs. static subunits

de Lichtenberg, Jensen et al., Science, 2005

just-in-time assembly

de Lichtenberg, Jensen et al., Cell Cycle, 2007

evolutionary flexibility

orthologs and paralogs

Jensen, Jensen, de Lichtenberg et al., Nature, 2006

protein complexes

Jensen, Jensen, de Lichtenberg et al., Nature, 2006

exercise 3

http://cyclebase-string.jensenlab.org

network expansion

what does SML1 do?

when is SML1 expressed?

how does that make sense?

multi-layer regulation

phosphorylation

CDK substrates

low-throughput data

high-throughput data

NetPhosK

correlation

Jensen, Jensen, de Lichtenberg et al., Nature, 2006

Jensen, Jensen, de Lichtenberg et al., Nature, 2006

bias

correlated changes

removes the bias

Jensen, Jensen, de Lichtenberg et al., Nature, 2006

co-evolution

disease networks

human proteins

>8,000 disease terms

text mining

co-mentioning

exercise 4

http://diseases.jensenlab.org

TYMS disease associations

inspect the evidence

colorectal cancer network

chemical networks

STITCH

STRING + chemicals

PubChem compounds

>74,000 small molecules

experimental data

BindingDB

ChEMBL

PDSP KiPsycoactive Drug Screening Program

PDBProtein Data Bank

drug targets

CTDComparative Toxicogenomics Database

DrugBank

GLIDAGPCR-Ligand Database

Matador

TTDTherapeutic Target Database

metabolic pathways

BioCyc

KEGGKyoto Encyclopedia of Genes and Genomes

Reactome

text mining

co-mentioning

NLPNatural Language Processing

same issues as for proteins

only worse

exercise 5

http://stitch-db.org

chemical network for TYMS

Kuhn et al., Nucleic Acids Research, 2012

network expansion

which role has thymidylate?

which role has dUMP?

which role has Pemetrexed?