Living cells sense and respond to physical forces that are mediated through their microenvironment. In vivo, these physical forces arise through the agencies of substrate adhesion, substrate stretch, and substrate rigidity, as well as through cell-cell contacts. To reproduce these physical forces within in-vitro cultures, my laboratory has developed novel nanotechnologies. Using these technologies, we have uncovered altogether novel phenomenon to describe how living cells contract, deform and communicate. In the etiology of excessive airway narrowing during asthma or endothelial cell barrier disruption during vascular disease these phenomena are ever-present, inescapable and dominant.
Jan 19: Daniel Needleman, Harvard University
Cell Biology and Active Liquid Crystals: Reevaluating the Tactoid Hypothesis
of Spindle Structure
Host: Tarun Kapoor
Jan 26: Aleksandra Walczak, Princeton University
Information Processing in Small Gene Regulatory Networks and Cascades
Host: M. Magnasco
Many of the biological networks inside cells can be thought of as transmitting information from the inputs (e.g., the concentrations of transcription factors or other signaling molecules) to their outputs (e.g., the expression levels of various genes). On the molecular level, the relatively small concentrations of the relevant molecules and the intrinsic randomness of chemical reactions provide sources of noise that set physical limits on this information transmission. Given these limits, not all networks perform equally well, and maximizing information transmission provides a optimization principle from which we might hope to derive the properties of real regulatory networks. I will discuss the properties of specific small networks that can transmit the maximum information. Concretely, I will show how the form of molecular noise drives predictions not just of the qualitative network topology but also the quantitative parameters for the input/output relations at the nodes of the network. In an attempt to link these general theoretical considerations to real biological systems, I will illustrate the predictions on the example of transmission of positional information in the early development of the fly embryo. Lastly, I will discuss different approaches of how a stochastic molecular level description can be successfully expanded to larger regulatory systems.
Feb 2: Konstantin Mischaikow, Rutgers University
A Databases schema for the global dynamics of multiparameter nonlinear systems
Host: E. Siggia
Feb 8: Bernardo Pando, MIT (2PM, coffee prior)
Contribution of gene duplications to the evolution of genetic networks
Probing mechanical principles of focal contacts in cell-matrix adhesion in a coupled stochastic-elastic modeling framework
Host: N. Arkus
Cell-matrix adhesion depends on the collective behaviors of clusters of receptor-ligand bonds called focal contacts between cell and extracellular matrix. While the behavior of a single molecular bond is governed by statistical mechanics at the molecular scale, continuum mechanics should be valid at a larger scale. In this seminar, an overview will be given over a series of recent theoretical studies aimed at probing the basic mechanical principles of focal contacts in cell-matrix adhesion via stochastic-elastic models in which stochastic descriptions of molecular bonds and elastic descriptions of interfacial traction/separation are unified in a single modeling framework. The objective is to illustrate these principles using simple analytical and numerical models. The discussions are organized around the following questions: Why is there a micron-scale size limit on focal adhesions? Why do cells prefer stiffer substrates? How does the stability of focal adhesions depend on the stress fiber orientation? Why are cytoskeletal contractile forces necessary to stabilize focal adhesions? With these curiosities in mind, the effects of cluster size, cell/matrix elastic modulus, loading direction and cytoskeletal contractility on the lifetime of adhesion clusters have been systematically investigated, with results showing that intermediate adhesion size, stiff substrate, cytoskeleton stiffening, low-angle pulling and moderate cytoskeletal pretension are factors that contribute to stable focal adhesions. These results provide feasible explanations for a wide range of experimental observations and suggest possible mechanisms by which cells can actively control adhesion and de-adhesion via cytoskeletal contractile machinery in response to mechanical properties of their surroundings.
Thur. Feb 11: Alexander Grosberg, NYU
Large scale organization of DNA in chromosomes
Host: P. Kumar
Feb 16: Alex Hoffman, UCSD
A Temporal Code in Inflammatory Signaling
Host: E. Siggia
Feb 17 (NOTE SPECIAL TIME: 1PM, coffee prior): Jingshan Zhang, Harvard University
Optimality and evolution: from proteome size to affinity maturation
Host: E. Siggia
Feb 19 (NOTE SPECIAL TIME: 2PM, coffee prior): Jingshan Zhang, Harvard University
Statistical mechanics and next-generation sequence assembly
Host: E. Siggia
Feb 23: Pankaj Mehta, Princeton University
From biological networks to complex behaviors
Host: E. Siggia
It is now clear that Phil Anderson’s famous maxim “More is Different” holds true even in biology. For example, microbiologists now agree that bacteria commonly engage in complicated collective behaviors that require individual cells to receive, interpret, and respond to information from one another and their environment. Underlying these behaviors are complex biological signaling networks. Understanding these signaling networks poses interesting new physics problems. In this talk, I will discuss two examples from my own research: 1) how the identification of transcription factor binding sites naturally leads to fascinating questions about the “inverse” statistical mechanics of hard rods in a disordered potential and 2) how we can use methods from information theory and statistical physics for quantifying the information processing capabilities of the Vibrio harveyi quorum sensing network.
The biophysical properties of contractile actomyosin networks play a predominate role in the ability of adherent cells to regulate how mechanical forces are sensed and generated at points of adhesion to the extracellular matrix. Although much is known about the mechanochemistry of individual myosin II motors and actin filaments, little is known how these properties drive the self assembly and biophysical properties of larger length scale networks and bundles that span the entire cell. Furthermore, the requirements of passive actin filament cross-linking in generating contractile structures is unknown. To address how myosin-II ATPase activity drives the dynamic organization of the F-actin cytoskeleton into structures capable of efficient force transmission, we have studied the dynamics and biophysical properties of actomyosin networks both in live cells and reconstituted networks of purified proteins. These studies isolate the minimal set of proteins and biophysical parameters required for regulating contractile matter.
Mar 2: David Kleinfeld, UCSD
One vessel, one stroke? Redundancy versus fragility in cortical vascularization
Cellular organization and function of a bacterial biochemical pathway
Host: M. Magnasco
Cells need to perform and regulate in a confined space a myriad of biochemical reactions. The variability due to fluctuations in enzyme levels is in part smoothened by the architecture of biochemical networks . However, no detailed molecular explanation for this effect is known. While trying to determine how the spatio-temporal distribution of enzymes from a metabolic cascade optimizes their function inside a cell, the central questions are: What is the intracellular organization of enzymes allowing efficient and non-interfering chemical reactions? What are the molecular interactions permitting these reactions? The study of cell wall synthesis during sporulation in the bacterium Bacillus subtilis is a good system to start answering these questions.
Self-assembly of DNA into nanoscale three-dimensional shapes
Host: N. Arkus
I will present a general method for solving a key challenge for nanotechnology: programmable self-assembly of complex, three-dimensional nanostructures. Previously, scaffolded DNA origami had been used to build arbitrary flat shapes 100 nm in diameter and almost twice the mass of a ribosome. We have succeeded in building custom three-dimensional structures that can be conceived as stacks of nearly flat layers of DNA. Successful extension from two-dimensions to three-dimensions in this way depended critically on calibration of folding conditions. We also have explored how targeted insertions and deletions of base pairs can cause our DNA bundles to develop twist of either handedness or to curve. The degree of curvature could be quantitatively controlled, and a radius of curvature as tight as 6 nanometers was achieved. This general capability for building complex, three-dimensional nanostructures will pave the way for the manufacture of sophisticated devices bearing features on the nanometer scale.
