Institute for Theoretical Biology

1
Institute for Theoretical Biology
Peter Hammerstein Evolution Organismic
Systems Andreas V. M. Herz - Computational
Neuroscience Hanspeter Herzel - Molecular
Cellular Evolution
Junior Research Groups Laurenz Wiskott Neural
Computation Michal Or-Guil Systems
Immunology Richard Kempter Theoretical
Neuroscience
2
Institute for Theoretical Biology
Teaching (100 25 students in biology
biophysics)
Basic courses Mathematics Statistics for
Biologists Theoretical Biology A (Modeling), B
(Evolution) Advanced courses Computational
Neuroscience I-IV, Data Analysis, Nonlinear
Dynamics, Bioinformatics, Evolutionary Game
Theory, Theoretical Immunology etc. (lectures,
computer exercises, seminars)
3
Nils Blüthgen, Szymon Kielbasa, Branka Cajavec,
Maciej Swat, Sabine Becker-Weimann, Matthias
Futschik, Didier Gonze, Samuel Bernard, Hanspeter
Herzel Institute for Theoretical Biology,
Humboldt-Universität Berlin
Major collaborators Christine Sers, Reinhold
Schäfer, Achim Kramer, Erich Wanker Charite
Berlin, MDC
Support BMBF Networks Proteomics Systems
Biology, SFB Theoretical Biology (Projects A3,
A4, A5), Stifterverband, GK Dynamics and Evolution
4
Current Research Projects

• RAS signaling cascades, target genes, promoter
  analysis, DNA methylation
• Circadian clock modeling the mammalian core
  oscillator, synchronization
• Huntington disease DNA-arrays, protein
  interaction networks, modeling aggregation and
  feedback loops

5
Model of Raf/Mek/Erk Signaling Cascade
Each reaction modeled by mass-action kinetics E
S ES E P Michaelis-Menten
kinetics problematic due to similar
concentrations of substrates and enzymes
Translate into ordinary differential equations
dS/dt - k1 SE k2 SE 13 equations
and about 40 parameters
6
Overexpression of Erk Sustained Oscillations
physiologically relevant? circadian clocks, cell
cycle, Hes1 somite oscillator
7
Oscillations after 1 h RAS induction?
?
Timescale of days hints to transcriptional
feedback MKPs?
8
Currently Identifying negative feeback loops
microarray time series RNAi for identification
of feedback loops
customized RAS target cDNA array 293 genes (3
spots/gene)
Zuber,J., ..., Schäfer,R. (2000). Nature
Genetics 24, 144-152.  
9
Light synchronizes the clock
The system
Regulation of physiology and behavior
Synchronization of peripheral clocks
10
Simplified model of the circadian core oscillator
S. Becker-Weimann et al. submitted
11
Comparison with experimental observations
Wildtype simulations reproduce period,
amplitudes, phase relations Per2 mutant (less
positive feedback) arythmic Per2/Cry2 double
knock-out rescue of oscillations
12
Data generation
Circadian oscillation of fibroblasts can be
monitored in living cells
Per1 E-box_luc Bmal1_luc
n 1
Experiments in Kramer Lab (Charite)
13
Huntington Chorea - Gene expression profiles and
modeling aggregation and feedbacks
Prolonged polyglutamine stretches in Huntingtin
lead to aggregate formation (nucleation via
positive feedback) Feedbacks via transcription
factors, caspases, proteasome inhibition Work
in progress Analysis of hybridized Affymetrics
chips Hybridization of cDNA microarray
chip Monitoring influence of aggregate formation
on gene expression Modelling of aggregate
formation and feedback loops
14
(No Transcript)
15
Modelling of Aggregation in Huntington's Disease
Nucleation Model
16
Models for Htt Aggregation (Cont'd)
Positive feedback on Htt cleavage
17
Modeling the G1/S Transition of the Mammalian
Cell Cycle
Maciej Swat et al. Proceedings GCB 2003
18
Simulation Results of G1/S Model

Bistability in the pRB-E2F core model
eee