Microtubules and Molecular Motors Do The Wave

Most people are familiar with audiences in crowded arenas performing “the wave,” raising their hands in sync to produce a pattern that propagates around the whole stadium.  This self-organized motion appears seemingly out of nowhere.  It is not produced by any external control, but is rather emerges from thousands of individuals interacting only with their neighbors.  A similar principle of self-organization might also be relevant on length scales that are billion times smaller.  On this scale, nanometer-sized proteins interact with each other to produce dynamical structures and patterns that are essential for life—and some of these processes are reminiscent of waves in crowded stadiums.  For example, thousands of nano-sized molecular motors located within a single eukaryotic flagellum or cilium coordinate their activity to produce wave-like beating patterns.  Furthermore, dense arrays of cilia spontaneously synchronize their beating to produce metachronal waves.

Proper functioning of cilia is essential for health; for example, cilia determine the correct polarity and location of our organs during development.  Defective cilia can cause a serious condition called situs inversus, in which the positions of the heart and lungs are mirrored from the normal state.  In another example, thousands of cilia in our lungs function to clear airways of microscopic debris such as dust or smoke by organizing their beating into coordinated, wave-like patterns.  Despite the importance of ciliar function, the exact mechanisms that lead to spontaneous wave-like patterns within isolated cilia, as well as in dense ciliary fields, is not well understood.

In a paper published in the journal Science this week, an interdisciplinary team consisting of physics graduate student Timothy Sanchez and biochemistry graduate student David Welch working with biophysicist Zvonimir Dogic and biologist Daniela Nicastro present a striking finding: the first example of a simple microscopic system that self-organizes to produce cilia-like beating patterns.  Their experimental system consists of three main components: 1) microtubule filaments; 2) motor proteins called kinesin, which consume chemical fuel to move along microtubules; and (3) a bundling agent that induces assembly of filaments into bundles.  Sanchez et al. found that under a certain set of conditions, these very simple components are able to self-organize into active bundles that spontaneously beat in a periodic manner.  One large spontaneously beating bundle is featured below:

In addition to observing the beating of isolated bundles, the researchers were also able to assemble a dense field of bundles that spontaneously synchronized their beating patterns into traveling waves.  An example of this higher-level organization is shown here:

The significance of these observations is several-fold. First, due to the importance of ciliar function for health, there is great interest in elucidating the mechanism that controls the beating patterns of isolated cilia as well as dense ciliary fields.  However, the complexity of these structures presents a major challenge.  Each eukaryotic flagellum and cilium contains more than 600 different proteins.  For this reason, most previous studies of cilia and flagella have employed a top-down approach; they have attempted to elucidate the beating mechanism by deconstructing the fully functioning organelles through the systematic elimination ­­­of constituent proteins. In this study, the researchers utilize an alternative bottom-up approach and demonstrate for the first time that it is possible to construct artificial cilia-like structures from a “minimal system,” comprised of only three components.  These observations suggest that emergent properties, spontaneously arising when microscopic molecular motors interact with each other, might play a role in formation of ciliary beating patterns.

Second, self-organizing processes in general have recently become the focus of considerable interest in the physics community.  These processes range in scale from microscopic cellular functions and swarms of bacteria to macroscopic phenomena such as flocking of birds and manmade traffic jams. Theoretical models indicate that these vastly different phenomena can be described using similar theoretical formalisms.  However, controllable experiments with flocks of birds or crowds at football stadiums are virtually impossible to conduct.  The experiments described by Sanchez et al. could serve as a model system to test a broad range of theoretical predictions. Third, the reproduction of such an essential biological functionality in a simple in vitro system will be of great interest to the fields of cellular and evolutionary biology. Finally, these findings open the door for the development of one of the major goals of nanotechnology: to design motile nano-scale objects.

These encouraging results are only the first from this very new model system.  The Dogic lab is currently planning refinements to the system to study these topics in greater depth.

UPDATE: Today, this publication was additionally featured on NPR Science Friday as the video pick of the week:

 

and more and more papers

More papers appearing recently, not otherwise mentioned:

  • Standfuss J, Edwards PC, D’Antona A, Fransen M, Xie G, Oprian DD, Schertler GF. The structural basis of agonist-induced activation in constitutively active rhodopsin. Nature. 2011;471(7340):656-60.
  • Rim Noh S, Lohani M, Isaacowitz DM. Deliberate real-time mood regulation in adulthood: The importance of age, fixation and attentional functioning. Cogn Emot. 2011:1-16.
  • Zemskov EP, Kassner K, Tsyganov MA, Epstein IR. Speed of traveling fronts in a sigmoidal reaction-diffusion system. Chaos. 2011;21(1):013115.
  • and MORE…

Is it the clock’s fault?

Brandeis researchers Jerome Menet and Professor Michael Rosbash (Biology Dept., Natl. Ctr. for Behavioral Genomics, and HHMI) review the relationships between psychiatric disease and the circadian clock in a review entitled “When brain clocks lose track of time: cause or consequence of neuropsychiatric disorders“. This review appeared recently in Current Opinion in Neurobiology. They discuss an increasing body of evidence that disorders in the clock may be directly involved in the etiology of these disorders.

Brandeis in Aspen I: String theory and quantum information

The Aspen Center for Physics is a physics retreat in which groups of researchers in a given field gather for a few weeks during the summer to discuss the latest developments and create the next ones. This May, a record four Brandeis physicists — almost a quarter of the department — visited the Center at the same time, attending two different workshops. This posting is about a workshop attended by string theorists Matthew Headrick and Albion Lawrence (and co-organized by Headrick);  another posting will describe a workshop attended by condensed-matter theorists Aparna Baskaran and Bulbul Chakraborty (a member of the Center’s advisory board).  Entry into Aspen workshops is competitive, so this strong Brandeis representation is remarkable; as always, we punch above our weight.

Headrick and Lawrence attended the workshop Quantum information in quantum gravity and condensed matter physics.  This was a highly interdisciplinary workshop, which brought together specialists in quantum gravity, including Headrick and Lawrence; experts in quantum information theory; and experts in “hard” condensed matter physics (who study material properties for which quantum phenomena play a central role).

Quantum information theorists study how the counterintuitive features of quantum mechanics — such as superpositions of states, entanglement between separated systems, and the collapse of the wave function brought on by measurement — could be exploited to produce remarkable (but so far mostly hypothetical) technologies like teleportation of quantum states, unbreakable encryption, and superfast computation. What does this have to do with gravity? When we try to formulate a consistent quantum-mechanical theory of gravity — which would subsume Einstein’s classical general theory of relativity — the concept of information crops up in numerous and often puzzling ways. For example, Stephen Hawking showed in the 1970s that, on account of quantum effects, black holes emit thermal radiation. Unlike the radiation emitted by conventional hot objects, which is only approximately thermal, pure thermal radiation of the kind that Hawking’s calculation predicted cannot carry information. Many physicists (including Hawking) therefore originally interpreted his result as implying that black holes fundamentally destroy information, challenging a sacred principle of physics. Today, based on advances in string theory, physicists (including Hawking) generally believe that in fact black holes do not destroy the information they contain.  Rather, black holes hide information in very subtle ways, by scrambling, encryption, and perhaps quantum teleportation — in other words, the same kinds of tricks that the quantum information people have been inventing and studying independently at the same time.

Another connection between gravity and information is provided by the so-called “holographic principle”, which also arose in the study of black holes and which has been given a precise realization in the context of string theory. This principle posits that, due to a combination of gravitational and quantum effects, there is a fundamental limit to the amount of information (i.e. the number of bits) that can be stored in a region of space, and furthermore that limit is related to its surface area, not its volume. String theorists, beginning with the seminal work of Juan Maldacena, have uncovered a number of precise implementations of this principle, in which certain quantum theories without gravity are holograms of theories of quantum gravity.  This should provide an avenue for uncovering the “tricks” gravity uses to hide information, a subject Lawrence is active in.  An additional benefit of these implementations is that calculations in the nongravitational theories which seemed prohibitively difficult become fairly simple in the gravitational side; these include  the computation of interesting quantities in quantum information theory, an area in which Headrick has done influential work.

All of these issues and many others were discussed in Aspen. This rather unique workshop was a very fruitful exchange of ideas, with physicists from three fields learning from each other and forging new interdisciplinary collaborations, in a setting where the scenery matched the grandeur of the subject.

From bench to clinical trials: the rFIXFc story

BrandeisNOW has a new story about the development of recombinant Factor IX Fc,  a candidate drug for hemophila, currently in Phase III cliniical trials. The story behind the Fc fusion technology started in academic labs including Neil Simister‘s at Brandeis, led to a biotech startup (Syntonix), which was then acquired by Biogen Idec, who are now conducing clinical trials.

For more, see http://www.brandeis.edu/now/2011/june/hemophilia.html

Trimethoprim decorated beads for magnetically manipulating mammalian cells

Brandeis grad students Yue Pan (Chemistry) and Marcus Long (Biochemistry), together with postdoc Hsin-Chieh Lin and Professors Lizbeth Hedstrom and Bing Xu, have extended their previous work on 6 nm diameter magnetic nanobeads (comparable in size to a globular protein). They’ve shown that when decorated with the ligand trimethoprim, the nanobeads can be used to selectively bind to target E coli DHFR fusion proteins, and in addition can be used to manipulate live cells with a magnetic force. This work entitled “Cell Compatible Trimethoprim (TMP)-Decorated Iron Oxide Nanoparticles Bind Dihydrofolate Reductase (DHFR) for Magnetically Modulating Focal Adhesion of Mammalian Cells” is now online in the Journal of the American Chemical Society (JACS).

These small, magnetic beads are the first example of solid supported trimethoprim and have numerous advantages over larger traditional beads, including rapid purification, and ultra low non-specific binding. It is, however, their ability to affect live cells that is most important. In the paper they first show that Cos-1 and HeLa cells can be incubated with the beads for over 5 days with little cell death. These cells can subsequently be manipulated by transfection. Finally when exposed to a magnetic force, the focal adhesion of bead-treated Cos-1 cells can be manipulated.

See also: recommendation at Faculty of 1000

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