Pump without pumps

By Kun-Ta Wu, Ph.D.

Pumping water through a pipe solves the need to provide water in every house. By turning on faucets, we retrieve water at home without needing to carry it from a reservoir with buckets. However, driving water through a pipe requires external pressure; such pressure increases linearly with pipe length. Longer pipes need to be more rigid for sustaining proportionally-increased pressure, preventing pipes from exploding. Hence, transporting fluids through pipes has been a challenging problem for physics as well as engineering communities.

To overcome such a problem, Postdoctoral Associate Kun-Ta Wu and colleagues from the Dogic and Fraden labs, and Brandeis MRSEC doped water with 0.1% v/v active matter. The active matter mainly consisted of kinesin-driven microtubules. These microtubules were extracted from cow brain tissues. In cells, microtubules play an important role in cell activity, such as cell division and nutrient transport. The activity originates from kinesin molecular motors walking along microtubules. In cargo transport, microtubules are like rail tracks; kinesin motors are like trains. When these tracks and trains are doped in water, their motion drives surrounding fluids, generating vortices. The vortices only circulate locally; there is no global net flow.

Wu-Pump without Pumps

Figure: Increasing the height of the annulus induces a transition from locally turbulent to globally coherent flows of a confined active isotropic fluid. The left and right half-plane of each annulus illustrate the instantaneous and time-averaged flow and vorticity map of the self-organized flows. The transition to coherent flows is an intrinsically 3D phenomenon that is controlled by the aspect ratio of the channel cross section and vanishes for channels that are either too shallow or too thin. Adapted from Wu et al. Science 355, eaal1979 (2017).

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Nature News Feature Highlights Dogic Lab Active Matter Research

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Biological material is constantly consuming energy to make things move, organize information such as DNA, or divide cells for reproduction; but building a fundamental theory which encompasses all of the features of biological matter is no easy task. The burgeoning field of active matter aims to understand these complex biological phenomena through physics. Active matter research has seen rapid growth over the last decade, but linking existing active matter theories with experimental tests has not been possible until recently. An explosion of biologically based and synthetic experimental systems as well as more detailed theories have arrived in recent years, and some of these foundational experiments have been conducted here at Brandeis University. Recently, a Nature News Feature (The Physics of Life) has highlighted work from Zvonimir Dogic’s lab in an article about the field of active matter and the physics which endeavors to understand biology.


Deep inside a worm’s nose

In a new paper in eLIFE, a team spearheaded by Brandeis postdocs David Doroquez and Cristina Berciu provide a strikingly detailed look at key structures called cilia on neurons involved in sensory perception in the nematode C. elegans. Primary cilia are the antenna-like structures onsensory neurons that gather information about the animal’s environment, such as chemicals, temperature, humidity, and touch. The genetic tools available to manipulate individual, identifiable neurons in C. elegans make worms an excellent model organism to study the assembly and function of cilia. This study requires a description of the structure of the cilia and their immediate surrounding glial support cells, and this new paper, a collaboration of the Sengupta and Nicastro labs, provides high-resolution 3D models showing how diverse and specialized these structures are.


A bouquet of sensory antennae. The 3D ultrastructure of all sensory cilia
and other neuronal projections in the head of the soil roundworm C.
elegans have been reconstructed using serial section transmission electron
microscopy. Shown are 3D isosurface-rendering models emerging from a
transmission electron microscopic cross-section of the worm.

The key techniques in this study were serial section transmission electron microscopy and electron tomography, with structures well-preserved by high-pressure freezing and freeze-substitution. With these techniques, the authors achieved the first high-resolution 3D reconstructions of 50/60 cilia from C. elegans. They describe several previously uncharacterized features — for example, there are distinct types of branching patterns – in one, the two cilia originate from independent basal bodies (as previously seen in Chlamydomonas). In the second, the cilia branch after the basal transition zone, the ciliary gatekeeper region. In the latter case, this basically means that whatever is needed for the cilia to branch has to be transported through the transition zone, suggest there might be novel mechanisms of ciliary protein trafficking. In a third pattern, the branching occurs proximally before the transition zone, and represent therefore dendritic microvilli, rather than ciliary branching. The study also showed different organizations  of microtubules in different cilia types and vesicles in regions of the cilia which have never been seen before, again pointing to new mechanisms of protein transport. They also describe new cilia-glial interactions, which might suggest that cilia and glia talk to each other.

For more about these structures (with lots of pretty pictures and movies), see:

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:


Prolonging assembly through dissociation

Microtubules are semiflexible polymers that serve as structural components inside the eukaryotic cell and are involved in many cellular processes such as mitosis, cytokinesis, and vesicular transport. In order to perform these functions, microtubules continually rearrange through a process known as dynamic instability, in which they switch from a phase of slow elongation to rapid shortening (catastrophe), and from rapid shortening to growth (rescue). The basic self-assembly mechanism underlying this process, assembly mediated by nucleotide phosphate activity, is omnipresent in biological systems.  A recent paper, Prolonging assembly through dissociation: A self-assembly paradigm in microtubules ,  published in the May 3 issue of Physical Review E,  presents a new paradigm for such self-assembly in which increasing depolymerization rate can enhance assembly.  Such a scenario can occur only out of equilibrium. Brandeis Physics postdoc Sumedha, working with Chakraborty and Hagan, carried out theoretical analysis of a stochastic hydrolysis model to demonstrate the effect and predict features of growth fluctuations, which should be measurable in experiments that probe microtubule dynamics at the nanoscale.

Model for microtuble dynamics. All activity is assumed to occur at the right end of the microtubule (denoted as ">")

The essential features of the model that leads to the counterintuitive result of depolymerization helping assembly are (a) stochastic hydrolysis that allows GTP to transform into GDP  in any part of the microtubule, and (b) a much higher rate of GTP attachment if the end of the microtubule has a GTP-bound tubulin dimer, compared to a GDP-bound tubulin dimer.    Process (a) leads to islands of GTP-bound tubulins to be buried deep in the microtubule.   Depolymerization from the end reveals these islands and enhances assembly because of the biased attachment rate (b).  The simplicity of the model lent itself to analytical results for various aspects of the growth statistics in particular parameter regimes.   Simulations of the model supported these analytical results, and extended them to regimes where it was not possible to solve the model analytically.  The statistics of the growth fluctuations in this stochastic hydrolysis model are very different from “cap models” which do not have GTP remnants buried inside a growing microtubule.   Testing the predictions in experiments could, therefore, lead to a better understanding of the processes underlying dynamical instability in-vivo and in-vitro.   An interesting question to explore is whether the bias in the attachment rates is different under different conditions of microtubule growth.

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