ParthasarathyLab
Biophysics & Soft Condensed Matter
Research
We construct experiments to explore a variety of topics in Biophysics and Soft Condensed Matter Physics. Throughout these fields, we encounter systems in which individually simple molecular components interact to give rise to complex, dynamic phenomena.
A glimpse of some of our research projects is given below.
Developmental Biophysics
How do cells organize themselves into complex tissues and organs in a developing animal?
How are geometry, mechanics, and biochemical signaling connected to give rise to robust, functional
forms? Building new sorts of microscopes for 3D imaging and examining early development in zebrafish,
a remarkable model organism, we're addressing these general questions, especially in the particular
contexts of bone formation and intestinal development.
Much of our work focuses on understanding the dynamics of microbial colonization of the
gut. You, like all animals, are host to trillions of microbes, and the formation of and
interactions among microbial communities remain largely mysterious. Our approach
to this topic involves imaging and extracting from images insights into
colony nucleation, growth, and competition. (This work is in collaboration with the group of
Karen Guillemin at UO.) We're part of a newly awarded (Sept. 2012) NIH Center for Systems Biology,
the press release for which
here.
Here's an example of our imaging of microbes:
Membrane Biophysics
Cellular membranes are remarkable materials -- flexible, two-dimensional fluids at which mobile, nanometer-scale proteins play reactive and structural roles (see illustration). How do the material properties of membranes -- their rigidity, the mobility of lipids and proteins, their various phase transitions -- contribute to their function and their ability to spatially organize? How do the unusual structures and compositions of the membranes of various organisms contribute to their survival?
Intracellular trafficking
The trafficking of cargo in cells involves dramatic transformations of membrane shape and topology by particular trafficking proteins. How do these proteins harness forces, energies, and local material properties to sculpt transport vesicles? How do proteins create curvature? Experiments in our lab seek to illuminate the mysterious mechanics of trafficking with experiments that directly construct, deform, and observe membranes interacting with trafficking proteins.
We have found that Sar1, a protein that regulates vesicle trafficking from the endoplasmic reticulum, lowers the rigidity of the lipid bilayer membrane to which it binds -- by up to as much as 100% as a function of its concentration. This is the first demonstration that a vesicle trafficking protein lowers the rigidity of its target membrane. Our experiments, illustrated below, involve using optically trapped microspheres to create membrane tethers whose properties reveal membrane mechanical properties.
Here's another movie that illustrates approaches to studying membrane mechanics:
The biophysics of tuberculosis -- Mycobacterial membrane mimics
Tuberculosis infects about one-third of the human population and kills two million people every year. It is a remarkably robust organism, capable for example of surviving for months under conditions of extreme dehydration. Mycobacteria, which include the species that cause tuberculosis and leprosy, have membranes that are unusual in both their structure and their composition. To examine the role the membrane may play in conferring to the bacteria their remarkable physical properties, we have created artificial solid-supported membranes that mimic these mycobacterial envelopes (see schematic, below). These mimics allow new sorts of quantitative examinations of their physical properties by enabling control of membrane composition and quantitative assays of membrane behavior.
We have discovered that trehalose dimycolate (TDM), a peculiar lipid present in all the mycobacteria, has the ability to make membranes resistant to dehydration. This is the first dehydration-resistant lipid ever reported. For details, see this paper (Harland et al., 2008) . More recently, together with our collaborators in Carolyn Bertozzi's group at UC Berkeley, we have examined synthetic mimics of TDM that replicate the dehydration-protection of the natural lipid; see this paper (Harland et al., 2009) for details.
Present work involves, among other things, the development of new functional materials that incorporate these remarkable lipids.
Membrane fluidity
Two-dimensional fluidity is one of the most important properties of biological membranes, as it allows lipids and proteins to interact with one another in spatially and temporally dynamic ways. Despite the importance of 2D mobility, its physical underpinnings are poorly understood, and 2D viscosity is very poorly quantified. We are exploring these topics using microrheological methods -- analyzing the Brownian motion of membrane-anchored particles.
Macromolecular structure
The orientation of macromolecules at cell surfaces is crucial to their interaction with soluble molecules, other cells, and the extracellular matrix. Proteins must project out from the dense pericellular forest for fruitful interactions to occur. The physical mechanisms that control protein orientation are not well understood. Using a well-controlled biomimetic model sytem of glycoprotein-like polymers (synthesized by our collaborators in the lab of Carolyn Bertozzi at UC Berkeley) together with interferometric techniques that yield nanometer-resolution of molecular orientation, we have been exploring the issue of orientation at membranes, finding, for example, a far greater sensitivity to molecular composition than expected (paper: Godula et al. 2009).
Controlling colloidal interactions
Can bio-membranes be used to create new, non-biological materials? We're interesting in using membrane-functionalization of microparticles as a means of controlling interparticle interactions and generating complex self-organized assemblies.
To reach these aims, we have invented new types of optical traps (see papers, Tietjen et al., 2008) that facilitate measurements of colloidal interactions and are developing additional approaches that will allow these composite particles to self-assemble into crystalline lattices.
Using our new traps, we have measured the pair-interaction energies of membrane-functionalized particles, demonstrating that lipid composition can, in fact, control inter-particle interactions. More remarkably, our ability to control surface properties with membranes yields surprising insights into the mystery of like-charge attraction -- the ability of colloidal particles with the same sign of charge to attract one another, which is (arguably) the greatest outstanding puzzle in colloidal physics. Details can be found in this paper (Kong & Parthasarathy, 2009). The image below illustrates two lipid-membrane-functionalized colloidal particles in an optical line trap.
Advanced Microscopy Techniques
To explore the above-mentioned topics, we use and also develop a variety of advanced optical microscopy techniques. These include methods based on interferometry, optical trapping, particle tracking, and more.
We've invented a new, fast, accurate, particle tracking method based on analytic determination of the radial-symmetry-center of a particle image. Please see our Particle Tracking page for the citation, software, and more.
--- Funding ---
We gratefully acknowledge support from the Alfred P. Sloan Foundation, the National Science Foundation, the Office of Naval Research through the Oregon Nanoscience and Microtechnologies Institute (ONAMI), and the M. J. Murdock Trust.