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?
