Biological Physics

Biron ​David Biron

Ph.D., Weizmann Institute, Israel, 2004.
Asst. Prof., 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. 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 a single cell. These small systems can potentially facilitate an understanding of basic principles of neural information processing and the regulation of behavior. In other words, it can be reasonably argued that C. elegans is a promising candidate for the title "the hydrogen atom of neuroscience".

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.

In broad strokes, the goal of our research is to contribute to a collective effort to truly understand small networks of neurons. Asymptotically, we identify this sought-after understanding with the ability to answer all of the questions about the system that might come to mind. These questions span multiple scales and various degrees of abstraction, from the molecular components of the system to the engineering and ingenuity of computing biological networks. This challenge must 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. Such detailed scrutiny is likely to spawn theoretical insights. It is our hope that these, in turn, will transcend the boundaries of small neural circuits and contribute to the thinking about more complex neural networks. At the same time, we believe that explaining small neural circuits is a worthy challenge in its own right.

Little is known about the regulation of the absence of movement, yet behavioral quiescent states are universal to the animal world with the most famous of these being sleep. It was recently discovered by David Raizen et al. that a C. elegans behavior termed lethargus bears behavioral similarities to sleep. We would like to contribute to establishing the nematode C. elegans as a novel model system for studying the genetic regulation of sleep. Is a novel, simple model organism for sleep genetics actually needed? Could C. elegans possibly be considered a potential model organism for sleep? We think that preliminary evidence suggests that this indeed may be the case - unequivocal proof is yet to be attained. It is currently unknown to what extent worms might be sharing sleep-regulatory mechanisms with more complex animals. In a nutshell, it is our job to help in finding out.

Is a novel, simple model organism for sleep genetics required? And why worms?

In recent years, the genetic analysis of sleep has emerged as an important discipline. It was realized that genetic manipulations are useful for dissecting specific components of this complex phenomenon. As a result, sleep research expanded its focus from mammalian model organisms to genetically tractable ones, such as the zebrafish D. rerio and the fruit fly D. melanogaster. Surprisingly, the fruit fly was shown to exhibit many fundamental features of mammalian sleep, and preliminary evidence suggests that the molecular mechanisms that regulate them may be phylogenetically ancient and evolutionarily conserved. The nematode C. elegans has unique advantages among genetically tractable models, which become crucial in the context of sleep research. The simplicity of the nervous system of the worm is of particular importance for the study of sleep, which is known to involve distributed neural circuits in Drosophila and in mammals. Moreover, the genetic regulation of sleep involves multiple coupled signaling pathways in both mammals and Drosophila. Therefore, the facile genetics and genomics possible in C. elegans, its optical transparency, and its short life cycle (allowing fast results) are additional key advantages. Taken together, they enable to systematically explore the molecular and neural substrates of C. elegans lethargus and to ask well-defined mechanistic questions that are inaccessible in other model organisms.

The idea that sleep is phylogenetically ancient enough to date back to nematodes, and that sleep genetics may be, at least in part, conserved between nematodes, arthropods and chordates has only recently been suggested. The assimilation of a new idea is seldom completed by a single person, and never overnight. It typically requires early adopters that partially abandon the traditional view and develop the novel point. That said, not every novel idea ends up being true – most don't… Preliminary evidence suggesting that worms may share sleep-regulatory pathways with more complex organisms does exist, but it is by no means conclusive. Notwithstanding commonalities in several regulatory signaling pathways, there are obviously differences between C. elegans lethargus and sleep. The primary expression of lethargus behavior, for instance, is not circadian but occurs during the four larval stages (although developing mammals too show non-circadian sleep cycles). By and large, the prevailing view is that the relevance of lethargus to mammalian sleep is questionable and that sufficient evidence for a direct link between the two is lacking. Identifying neurons and molecules that regulate lethargus and searching for evolutionary conservation will require considerable effort and commitment, while success is in no way guaranteed.

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 2/2011

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Margaret Gardel

​Margaret Gardel

Ph.D., Harvard University, 2004.
Associate Professor, Dept. Physics, Inst. for Biophysical Dynamics, James Franck Inst., and the College.
Experimental biophysics.

Margaret Gardel's homepage

We are interested in the physical properties of biological cells. 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 these macromolecular assemblies at sub-micron length scales to study how forces generated by individual proteins are transmitted to cellular length scales.

Cytoskeletal materials also provide 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. By reconstituting these networks from purified proteins in vitro, we can better understand these physical behaviors.

Selected Publications:

  • Dynamic and Structural Signatures of Lamellar Actomyosin Force Generation. Aratyn-Schaus Y, Oakes PW, Gardel ML. Molecular Biology of the Cell. 2011 22: 1330-1339 (PMID: 21307339) (pdf).
  • Cell-ECM Traction Force Modulates Endogenous Tension at Cell-Cell Contacts. Maruthamuthu V, Sabass B, Schwarz US, Gardel ML. Proc Natl Acad Sci U S A. 2011 Mar 22; 108 12: 4708-13 (PMID: 21383129) (pdf).
  • Shear Thickening of F-actin networks crosslinked with non-muscle myosin IIB. Norstrom M, Gardel ML. Soft Matter. 2011 7: 3228-3233.
  • Optimization of traction force microscopy for micron-sized focal adhesions. Stricker J, Sabass B, Schwarz US, Gardel ML. J Phys Condens Matter. 2010 Apr 26;22(19):194104. (PMID: 20523913) (pdf).

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Updated 4/2011

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Michael Rust

​Michael Rust

Ph.D., Harvard University, 2006.
Dept. of Molecular Genetics and Cell Biology, Dept. of Physics, Inst. for Genomics and Systems Biology, and the College.
Experimental biophysics, systems biology.

Michael Rust's homepage

Living cells are capable of remarkably sophisticated behavior, combining information from the external environment with an internally stored model of past events to make decisions about how to respond to challenges. These decisions can be thought of as information processing tasks that must occur robustly in the face of various potentially disruptive fluctuations in the conditions inside the cell. Fundamentally, these computations are carried about by networks of proteins and nucleic acids, specialized macromolecular machines sculpted by evolution to channel specific chemical reactions.

We are interested in uncovering the design principles of these networks that allow them to function reliably. We are currently interested in the circadian rhythm, a nonlinear oscillator in living cells that is normally phase locked to the daily rhythms in the external environment and that coordinates cyclic behavior and metabolism in living organisms. We are exploiting a particularly powerful model system from cyanobacteria, where the core oscillator can be studed in a test tube using a mixture of three purified proteins (KaiA, KaiB, and KaiC). Our approach combines methodology from various disciplines including dynamical systems theory, engineering, biochemistry, and quantitative microscopy.

Selected Publications:

  • Light-driven Changes in Energy Metabolism Directly Entrain the Cyanobacterial Circadian Oscillator. M. J. Rust, S. S. Golden, E. K. O'Shea. Science 331, 2200-223 (2011).
  • Ordered Phosphorylation Governs Oscillation of a Three-Protein Circadian Clock. M. J. Rust, J. S. Markson, W. S. Lane, D. S. Fisher, E. K. O'Shea. Science 318, 809-812 (2007).
  • Sub-diffraction-limit Imaging by Stochastic Optical Reconstruction Microscopy (STORM). M. J. Rust, M. Bates, X. Zhuang. Nature Methods 3, 793-795 (2006).

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Updated 8/2012

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