Biological Physics

Biron​David Biron

Ph.D., Weizmann Institute, Israel, 2004.
Assistant Professor, Dept. of Physics, James Franck Institute, and the College.
Neuroethology of C. elegans,Neuroscience, Experimental biophysics.
David Biron's homepage

All living organisms obtain information about their environment, process it and respond with behavioral output. Often, but not exclusively, information processing is performed by networks of neurons in the brain. However, studying complex brains is extremely challenging both conceptually and technically, and tends to impose a coarse grained approach. Fortunately, some model systems exhibit non-trivial behavioral patterns that are governed by neuronal circuits of limited size. A handful of such identifiable neurons are ideal for a detailed scrutiny on multiple levels: from circuitry to individual molecules within single cells. They can thus facilitate the understanding of basic principles of neural information processing and the engineering of neural circuits. In other words, a model system combining small neural circuits and high experimental resolution is a promising candidate for the title "the phage of neuroscience" (or the hydrogen atom, if you will) and it could be reasonably argued that C. elegans is precisely that.

The nematode C. elegans possesses 302 neurons, the anatomy and connectivity of which are known with great precision. It was the first multi-cellular organism to have its genome fully sequenced and many of its genes have been cloned and characterized. Furthermore, a slew of existing genetic, genomic and biophysical techniques make it possible to perturb and assay this model organism with unparalleled experimental resolution. Specifically, it is possible to study concurrently the behavior of the entire animal, sub-circuits in its nervous system, individual neuron physiology and the molecules involved in intra-neuronal signaling pathways. Already on the seemingly elementary level of worm behavior not all is clear. For instance, the precise fashion by which the worm navigates its environment is not fully understood. More detailed questions regarding the manner by which nematodes sense their environment are only partially answered and a comprehensive picture of how their nervous system goes about processing the information provided by the sensory apparatus simply does not exist.

A good starting point for investigating the sensing of the environment and related navigational behavior is to focus on the responses of the worm to temperature stimuli, known as "thermotaxis". We combine molecular biology techniques, quantitative analysis, and optics and engineering methods in order to identify and characterize the components of the thermotaxis neural circuit and other sensory dependent navigation paradigms. We view them as models which we can use to shed light on fundamental questions such as the relative contributions of the intra- and inter-cellular scales to the function of the neural circuit, the coordinated regulation of gene expression that enables the homeostatic function of neurons in a noisy setting, the neuronal origin of stochastic behavioral patterns and the nature and limitations of information flow between neurons.

In a parallel effort we will use a similar combination of experimental approaches for the investigation of the recently reported sleep like behavior of worms. C. elegans molts its cuticle at the end of each of four developmental stages. Raizen et al. recently described the quiescent behavioral state that precedes each molt, as well as its similarities to sleep. Since the evolutionary origin and the very purpose of sleep are largely unknown our hope is that the combination of a powerful model system and our experimental tools will assist in unveiling at least part of the mystery.  

In broad strokes, the goal of our research is to contribute to a collective effort to truly understand small networks of neurons. Asymptotically, I identify this sought-after understanding with the ability to answer all of the questions about the  system that might come to mind, a small subset of which were presented here. These questions span multiple scales and various degrees of abstraction, from the molecular components of the system to the engineering and ingenuity of computational devices made of biochemical materials. This challenge must therefore be met with a  parallel effort of both forward (e.g., revealing the molecular components and their interactions in detail) and reverse (e.g., systems analysis of higher function and statistical properties) approaches. Similar to the case of bacterial chemotaxis, such detailed scrutiny is likely to spawn theoretical insights. It is my hope that these, in turn, will transcend the boundaries of small neural circuits and contribute to the thinking about more complex biological neural networks. At the same time, I believe that explaining the design and properties of information processing in the framework of small neural circuits is a worthy challenge in its own right.

Selected Publications:

  • Biron D. , Wasserman S., Thomas J. H., Samuel A. D. T. and Sengupta P. (2008) An olfactory neuron responds stochastically to temperature and modulates C. elegans thermotactic behavior. Proc Natl Acad Sci USA 105(31):11002-7
  • Biron D., Shibuya M., Gabel C., Brown A., Clark D.A., Wasserman S.M., Sengupta P. and Samuel A.D.T. (2006) Regulation of thermotactic behavioral plasticity by a diacylglycerol kinase in C. elegans. Nat Neurosci. 9(12):1499-505
  • Clark D. A., Biron D., Sengupta P. and Samuel A.D.T. (2006) The AFD sensory neurons encode multiple functions underlying thermotactic behavior in C. elegans. J Neurosci. 26:7444-51

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Updated 9/2008

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Margaret Gardel

​Margaret Gardel

Ph.D., Harvard University, 2004.
Assistant Professor, Dept. Physics, Inst. for Biophysical Dynamics, James Franck Inst., and the College.
Experimental biophysics.
Margaret Gardel's homepage

We are interested in the biological properties of the cytoskeleton of eukaryotic cells and how these regulate cell physiology. Cells generate protrusive and contractile forces in response to external chemical and mechanical stimuli and during cell migration. Improper regulation of the mechanical behavior of cells has been linked to a number of diseases, including asthma, cardiac arrhythmia and cancer metastasis.

The varied mechanical behavior of cells is determined by a dynamic and composite polymer network of > 100 proteins called the cytoskeleton. We develop tools to study the dynamic structure and biophysical behavior of macromolecular assemblies at sub-micron length scales to study how cells generate and transmit mechanical forces.

We use high resolution fluorescence microscopy to observe cytoskeletal protein dynamics in living cells and, simultaneously, measure their biophysical properties at micron length scales. By combining dynamic structure with biophysical measurements, we aim to elucidate the origins of the biophysical behavior of these assemblies. We are particularly interested in the biophysical behavior of contractile actomyosin networks and how these regulate how focal adhesion transmit force to the extracellular matrix.

Cytoskeletal material also provides quite a number of interesting problems in soft condensed matter physics. In contrast to traditional flexible polymers or rigid rods, cytoskeletal polymers are semi-flexible and the energy required to bend the filament on micron length scales is comparable to thermal energy. The competition between enthalpic and entropic effects in the dynamics and deformation of semi-flexible networks lead to extremely rich and varied mechanical response of both entangled solutions and chemically cross-linked networks. In the living cell, these networks are driven far from equilibrium by molecular motors and proteins that regulate filament cross-linking and assembly. We study the mechanical behavior of reconstituted networks of purified cytoskeletal proteins in vitro to better develop physical models of the elasticity of these dynamic semi-flexible polymer networks.

Selected Publications:

  • M.L. Gardel, F. Nakamura, J. Hartwig, J.C. Crocker, T.P. Stossel and D.A. Weitz, Pre-stressed F-actin Networks Cross-linked by Hinged Filamins Replicate Mechanical Properties of Cells, Proceedings of the National Academy of Sciences, 103 1762-1767 (2006).
  • M.L. Gardel, F. Nakamura, J. Hartwig, J.C. Crocker, T.P. Stossel and D.A. Weitz, Stress-Dependent Elasticity of Composite Actin Networks as a Model for Cell Behavior, Physical Review Letters, 96 088102 (2006).
  • J.H. Shin, M.L. Gardel, F.C. MacKintosh, L Mahadevan, P.A. Matsudaira and D.A. Weitz, Relating Microstructure to Elasticity of Cross-linked and Bundled Actin Networks, Proc. Nat'l Acad. Sci., 101 9637-9641 (2004).
  • M.L. Gardel, J.H. Shin, F.C. MacKintosh, L Mahadevan, P.A. Matsudaira and D.A. Weitz, Elastic Behaviors of F-actin Networks, Science, 304 1301-1305 (2004).
  • M.L. Gardel, J.H. Shin, F.C. MacKintosh, L Mahadevan, P.A. Matsudaira and D.A. Weitz, Scaling of the Rheology of Prestressed Networks as a Probe of Single Filament Elasticity, Physical Review Letters, 93 188102 (2004).

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Updated 10/2006

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