My research interests cover a broad range of topics in theoretical soft condensed matter, biological physics, and quantitative (systems) biology. On the one hand, I am studying the mechanical and dynamical properties of biological and soft condensed matter. Here, main themes of my research are morphological transitions, shape fluctuations and instabilities, and the emergence of order. On the other, I am using physical methods to investigate the physiological properties of microbiological subsystems. Here, the long-term goal is to establish quantitative links between molecular scales and cell physiology.
My lab is also part of the Center for Synthetic Microbiology (SYNMIKRO). In this center we closely collaborate with the experimental groups of A. Brune, H.-U. Mösch, L. Søgaard-Andersen and M. Thanbichler and the theoretical groups of S. Dahlke and B. Freisleben.
Current research topics
-Mechanical properties of biological matter
- Stability of phages and viral elasticity
- Cell motility
- Membrane fusion
-Bacterial Cellbiology- Cell division in bacteria (Caulobacter & Myxo)
- Protein oscillations
-Quantitative Biology
- Nitrogen assimilation in bacteria
- Physical aspects of bacterial metabolism
- Decision making in bacterial populations
-Physical Properties of Macromolecules
- Protein folding
- Protein-DNA interactions
-Dynamical Transitions in Soft Condensed Matter Systems
- Synchronization of ciliar beating
- Active membranes in confining geometries
-Physics Approaches to Cancer
- Analysis of gene expression data
- Development of predictors for cancer subtypes
Recent Publications (full list can be found here):
Stripe Formation in Bacterial Systems with
Density-Suppressed Motility
(with X. Fu et al. PRL 108, 198102 (2012))
Engineered bacteria in which motility is reduced by local cell
density generate periodic stripes of high and low density when
spotted on agar plates. We study theoretically the origin and mechanism
of this process in a kinetic model that includes growth and
density-suppressed motility of the cells. The spreading of a
region of immotile cells into an initially cell-free region is
analyzed. From the calculated front profile we provide an analytic
ansatz to determine the phase boundary between the stripe and the
no-stripe phases. The influence of various parameters on the phase
boundary is discussed.
Influence of molecular noise on the growth of single cells
and bacterial populations
(with M. Schmidt and M. Creutziger, PLoS One 7(1): e29932
(2012))
During the last decades experimental studies have revealed that
single cells of a growing bacterial population are significantly
exposed to molecular noise giving rise to significant cell-to-cell
variations. In this study we theoretically explore if there are
evolutionary benefits of noise for a growing population of
bacteria. We analyze different situations where noise is either
suppressed or where it affects single cell behavior. We consider
two specific examples that have been experimentally observed in
wild-type Escherichia coli cells: (i) the precision of division
site placement (at which molecular noise is highly suppressed) and (ii)
the occurrence of noise-induced phenotypic variations in
fluctuating environments. Surprisingly, our analysis reveals that in
these specific situations both regulatory schemes [i.e.
suppression of noise in example (i) and allowance of noise in example
(ii)] do not lead to an increased growth rate of the population.
Assuming that the observed regulatory schemes are indeed caused by
the presence of noise our findings indicate that the evolutionary
benefits of noise are more subtle than a simple growth advantage
for a bacterial population in nutrient rich conditions.
Sequential Establishment of Stripe Patterns in an
Expanding Cell Population
(with C. Liu et al. Science 334, 238 (2011), see also
press release)
Periodic stripe patterns are ubiquitous in living
organisms. We describe a synthetic genetic circuit
that couples cell density and motility. This system enabled
programmed Escherichia coli cells
to form periodic stripes of high and low cell densities
sequentially and autonomously.
Theoretical and experimental analyses reveal that the spatial
structure arises from a recurrent
aggregation process at the front of the continuously expanding
cell population. The number
of stripes formed could be tuned by modulating the basal
expression of a single gene. The
results establish motility control as a simple route to
establishing recurrent structures without
requiring an extrinsic pacemaker.
Temporal and spatial oscillations in
bacteria
(with L. Søgaard-Andersen,
Nature Reviews Microbiology 9, 565 (2011), see
also
press release)
Oscillations pervade biological systems at all scales. In
bacteria, oscillations control fundamental processes, including gene
expression, cell cycle progression, cell division, DNA segregation and
cell polarity. Oscillations are generated by biochemical oscillators
that incorporate the periodic variation in a parameter over time to
generate an oscillatory output. Temporal oscillators incorporate the
periodic accumulation or activity of a protein to drive temporal cycles
such as the cell and circadian cycles. Spatial oscillators incorporate
the periodic variation in the localization of a protein to define
subcellular positions such as the site of cell division and the
localization of DNA. In this Review, we focus on the mechanisms of
oscillators and discuss the design principles of temporal and spatial
oscillatory systems.
Protein Kinase C Inhibitor Sotrastaurin
Selectively Inhibits the Growth of CD79 Mutant Diffuse Large
B-Cell Lymphomas
(with T. Naylor, H. Tang, A. Enns, W. Schuler, B. Dörken, M.
Warmuth, G. Lenz, and F. Stegmeier, Cancer
Research 71, 2643 (2011)) The activated B-cell–like (ABC) subtype of diffuse large
B-cell lymphoma (DLBCL) correlates with poor prognosis. In
this study, we offer evidence of therapeutic potential for the
selective PKC (protein kinase C) inhibitor sotrastaurin (STN) in
preclinical models of DLBCL. A significant fraction of ABC DLBCL
cell lines exhibited strong sensitivity to STN, and we found that the
molecular nature of NF-kB pathway lesions predicted
responsiveness. our findings offer a strong rationale for the clinical
evaluation of STN in ABC DLBCL patients who harbor CD79 mutations
also illustrating the necessity to stratify DLBCL
patients according to their genetic abnormalities.
Transient binding of dynein controls bidirectional
long-range motility of early endosomes
(with M. Schuster, R. Lipowsky, M.-A. Assmann, G. Steinberg, PNAS 108, 3618 (2011))
(with M. Schuster, R. Lipowsky, M.-A. Assmann, G. Steinberg, PNAS 108, 3618 (2011))
In many cell types, bidirectional long-range endosome
transport is mediated by the opposing motor proteins dynein and
kinesin-3. Here we use a fungal model system to investigate how both
motors cooperate in early endosome (EE) motility. We fused the green
fluorescent protein to the endogenous dynein heavy chain and the kin3
gene and visualized both motors and their cargo in the living cells.
Whereas kinesin-3 was found on anterograde and retrograde EEs, dynein
motors localize only to retrograde organelles. Live cell imaging shows
that binding of retrograde moving dynein to anterograde moving
endosomes changes the transport direction of the organelles.
Theoretical modeling shows that the observed in vivo trajectories are
indeed compatible with a "loading on the run" mechanism.
Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse
large B-cell lymphoma cells
(with B. Kloo, D. Nagel, M. Pfeifer, M. Grau, M. Düwel, M. Vincendeau, B. Dörken, G. Lenz, and D. Krappmann, PNAS 108, 272 (2011)).
The activated B-cell–like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) represents a very aggressive human lymphoma entity. Here we report that constitutive activity of PI3K and the downstream kinase PDK1 are essential for the viability of two ABC DLBCL cell lines that carry mutations in the BCR proximal signaling adaptor CD79B. In these cells, PI3K inhibition reduces NF-κB activity and decreases the expression of NF-κB target genes.
A Geometrical Model for DNA Organization in
Bacteria
(with M. Buenemann, PLoS ONE 5(11): e13806)
In this paper we develop a geometrical model that explains the
observed linear correlation (of the bacterium Caulobacter) between the
spatial position of genes in the cellular volume and the position on
the chromosomal map.
Reversible Adenylylation of Glutamine Synthetase
Is Dynamically Counterbalanced during Steady-State Growth of
Escherichia coli
(with H. Okano, T. Hwa and D. Yan, J. Mol. Biol. (2010) 404,
522–536)
Glutamine synthetase (GS) is the central enzyme for nitrogen
assimilation in Escherichia coli and is subject to reversible
adenylylation (inactivation) by a bifunctional GS
adenylyltransferase/adenylyl-removing enzyme (ATase). Here, we
show that the adenylyl-removing (AR) activity of ATase is required
to counterbalance its AT activity during steady-state growth under
both nitrogen-excess and nitrogen-limiting conditions. The
results suggest that dynamic counterbalance by reversible covalent
modification may be a general strategy for controlling the
activity of enzymes such as GS, whose physiological output allows
adaptation to environmental fluctuations.
Analysis of single molecule folding studies with replica
correlation functions
(with S. Cho and P. Wolynes, Chem. Phys. Lett. 471 (2009) 310–314)
Single molecule experiments that can track individual trajectories of biomolecular processes provide a challenge for understanding how these stochastic trajectories relate to the global energy landscape. Using trajectories from a native structure based simulation, we use order parameters that accurately distinguish between protein folding mechanisms that involve a simple, single set of pathways versus a complex one with multiple sets of competing pathways. We show how the folding dynamics can be analyzed with replica correlation functions in a way that is compatible with single molecule experiments.
(with S. Cho and P. Wolynes, Chem. Phys. Lett. 471 (2009) 310–314)
Single molecule experiments that can track individual trajectories of biomolecular processes provide a challenge for understanding how these stochastic trajectories relate to the global energy landscape. Using trajectories from a native structure based simulation, we use order parameters that accurately distinguish between protein folding mechanisms that involve a simple, single set of pathways versus a complex one with multiple sets of competing pathways. We show how the folding dynamics can be analyzed with replica correlation functions in a way that is compatible with single molecule experiments.
Synchronization, phase locking, and metachronal wave
formation in ciliary chains
(with T. Niedermayer and B. Eckhardt, Chaos (2008), 037128)
We develop a simple model for ciliary motion that is complex enough to describe well the behavior of beating cilia but simple enough to study collective effects analytically. Beating cilia are described as phase oscillators moving on circular trajectories with a variable radius. This radial degree of freedom turns out to be essential for the occurrence of hydrodynamically induced synchronization of ciliary beating between neighboring cilia. The transitions to the synchronized and phase-locked state of two cilia and the formation of metachronal waves in ciliary chains with different boundary conditions are discussed.
(with T. Niedermayer and B. Eckhardt, Chaos (2008), 037128)
We develop a simple model for ciliary motion that is complex enough to describe well the behavior of beating cilia but simple enough to study collective effects analytically. Beating cilia are described as phase oscillators moving on circular trajectories with a variable radius. This radial degree of freedom turns out to be essential for the occurrence of hydrodynamically induced synchronization of ciliary beating between neighboring cilia. The transitions to the synchronized and phase-locked state of two cilia and the formation of metachronal waves in ciliary chains with different boundary conditions are discussed.
Mechanical limits of viral capsids
(with M. Buenemann, PNAS 104 (2007), 9925–9930)
We study the elastic properties and mechanical stability of viral capsids under external force-loading with computer simulations. We demonstrate how, in a combined numerical and experimental approach, the elastic parameters of specific phages can be determined with high precision. The experimentally observed bimodality of spring constants is shown to be of geometrical origin. We define a criterion for capsid breakage that explains well the experimentally observed rupture. We also discuss the influence of chirality and DNA packaging on the mechanical properties. Finally, we show how our numerically calculated energy maps can be used to extract information about the strength of protein–protein interactions from rupture experiments. [ pdf, suppl. mater,press release]
(with M. Buenemann, PNAS 104 (2007), 9925–9930)
We study the elastic properties and mechanical stability of viral capsids under external force-loading with computer simulations. We demonstrate how, in a combined numerical and experimental approach, the elastic parameters of specific phages can be determined with high precision. The experimentally observed bimodality of spring constants is shown to be of geometrical origin. We define a criterion for capsid breakage that explains well the experimentally observed rupture. We also discuss the influence of chirality and DNA packaging on the mechanical properties. Finally, we show how our numerically calculated energy maps can be used to extract information about the strength of protein–protein interactions from rupture experiments. [ pdf, suppl. mater,press release]
Kinetics of DNA-mediated docking reactions between
vesicles tethered to supported lipid bilayers
(with Y.-H. Chan and S. Boxer, PNAS 104 (2007), 18913–18918)
We intropduce a novel approach to study the dynamics of
membrane–membrane recognition that plays an important for processes
such as membrane fusion. We use DNA-tethered vesicles as a general
scaffold for displaying membrane components. This system was used to
characterize the docking reaction between two populations of tethered
vesicles that display complementary DNA. Deposition of vesicles onto a
supported lipid bilayer was performed by using a microfluidic device to
prevent mixing of the vesicles in bulk during sample preparation. Once
tethered onto the surface, vesicles mixed via two-dimensional
diffusion. DNA-mediated docking of two reacting vesicles results in
their colocalization after collision and their subsequent tandem
motion. Individual docking events and population kinetics were observed
via epifluorescence microscopy. A lattice-diffusion simulation was
implemented to extract from experimental data the probability that a
collision leads to docking. For individual vesicles displaying small
numbers of docking DNA this probability shows a first-order
relationship with copy number as well as a strong dependence on the DNA
sequence. Both trends are explained by a model that includes both
tethered vesicle diffusion on the supported bilayer and docking DNA
diffusion over each vesicle’s surface. These results provide the basis
for the application of tethered vesicles to study other membrane
reactions including protein-mediated docking and fusion.
(with Y.-H. Chan and S. Boxer, PNAS 104 (2007), 18913–18918)
We intropduce a novel approach to study the dynamics of
membrane–membrane recognition that plays an important for processes
such as membrane fusion. We use DNA-tethered vesicles as a general
scaffold for displaying membrane components. This system was used to
characterize the docking reaction between two populations of tethered
vesicles that display complementary DNA. Deposition of vesicles onto a
supported lipid bilayer was performed by using a microfluidic device to
prevent mixing of the vesicles in bulk during sample preparation. Once
tethered onto the surface, vesicles mixed via two-dimensional
diffusion. DNA-mediated docking of two reacting vesicles results in
their colocalization after collision and their subsequent tandem
motion. Individual docking events and population kinetics were observed
via epifluorescence microscopy. A lattice-diffusion simulation was
implemented to extract from experimental data the probability that a
collision leads to docking. For individual vesicles displaying small
numbers of docking DNA this probability shows a first-order
relationship with copy number as well as a strong dependence on the DNA
sequence. Both trends are explained by a model that includes both
tethered vesicle diffusion on the supported bilayer and docking DNA
diffusion over each vesicle’s surface. These results provide the basis
for the application of tethered vesicles to study other membrane
reactions including protein-mediated docking and fusion.
Current and Past Collaborators:
- Steve Boxer (Stanford)
- Jiandong Huang (Hong Kong)
- Terry Hwa (UCSD)
- Jean-François Joanny (Institut Curie, Paris) and Jacques Prost (ESPCI, Paris)
- Sydney Kustu (Berkeley)
- Daniel Riveline (Grenoble)
- Peter Swain (McGill)
- Yiping Wang (Bejing)
- Peter Wolynes (UCSD)
