Ivanovic Receives 2017 NIH Director’s New Innovator Award

photo: Mike Lovett

Assistant Professor of Biochemistry Tijana Ivanovic has received a 2017 NIH Director’s New Innovator Award. This award is part of the NIH’s High-Risk, High-Reward Research program, designed to fund early career investigators who propose innovative and potentially transformative projects. Ivanovic will receive $1,500,000 in direct costs over five years to spearhead a research program aimed at comprehensively characterizing molecular changes in the viral cell-entry protein hemagglutinin (HA) that define pandemic influenza viruses. With the generated insights, Ivanovic hopes to ultimately be in a position to predict the pandemic potential of influenza viruses circulating in nature.

HA densely covers the influenza virion surface, where it allows the virus to both recognize and penetrate (fuse with) the cells of its host. HA is also a key target of neutralizing antibodies that protect us from influenza infection. An influenza pandemic is characterized by the adaptation of a new HA subtype to cell entry into human cells (of what was originally an avian virus). Without the pre-existing immunity to protect us, the virus quickly spreads around the globe. During pandemic adaptation, both HA functions in target-cell recognition and membrane fusion undergo key molecular changes. Ivanovic will use a custom-built Total Internal Reflection Fluorescence Microscope (TIRFM) to visualize, in real time, individual virus particles as they engage and fuse with target cell membranes. This system will allow her to obtain large-scale quantitative information about distinct HA functions at an unprecedented level of detail. She will compare avian viruses with their evolutionary offspring that infected humans, including past pandemic strains. She hopes to develop models for predicting which viruses will lead to a major flu outbreak.

Ivanovic obtained a PhD in virology from Harvard University and carried out postdoctoral research with Stephen Harrison in molecular biophysics. She integrates these diverse backgrounds in her laboratory, where members are trained across these two and other synergistic areas (such as laser microscope optics, and analytical and computational modeling). The funds from the New Innovator award have created new opportunities for hiring, and the lab is actively recruiting postdocs, PhD students (from the Biochemistry and Biophysics, Molecular and Cell Biology, and Physics graduate programs) and undergraduate researchers to undertake this ambitious program.

Materials in Motion: Engineering Bio-Inspired Motile Matter

Life is on the move! Motion is ubiquitous in biology. From the gargantuan steps of an elephant to the tiniest single celled amoeba, movement in biology is a complex phenomenon that originates at the cellular level and involves the organization and regulation of thousands of proteins. These proteins do everything from mixing the cytoplasm to driving cell motility and cell division. Deciphering the origins of motion is no easy feat and scientists have been studying such complex behavior for quite some time. With biology as an inspiration, studying these complex behaviors provides insight into engineering principals which will allow researchers to develop an entirely new category of far-from-equilibrium materials that spontaneously move, flow or swim.

In a recent report in the journal Nature, a team of researchers from Brandeis University consisting of Tim Sanchez, Daniel T. N. Chen, Stephen J. DeCamp, Michael Heymann, and Zvonimir Dogic have constructed a minimal experimental system for studying far-from-equilibrium materials. This system demonstrates the assembly of a simple mixture of proteins that results in a hierarchy of phenomena. This hierarchy begins with extending bundles of bio-filaments, produces networks that mix themselves, and finally culminates in active liquid crystals that impart self-motility to large emulsion droplets.

Their system consists of three basic components: 1) microtubule filaments, 2) kinesin motor proteins which exert forces between microtubule filaments, and 3) a depletion agent which bundles microtubule filaments together. When put together under well-defined conditions, these components form bundled active networks (BANs) that exhibit large-scale spontaneous motion driven by internally generated active stresses. These motions, in turn, drive coherent fluid flows. These features bear a striking resemblance to a biological process called cytoplasmic streaming, in which the cellular cytoskeleton spontaneously mixes its content. Additionally, the system has great potential for testing active matter theories because the researchers can precisely tune the relevant system parameters, such as ATP and protein concentration.


The researchers also demonstrate the utility of this biologically-inspired synthetic system by studying materials science topics that have no direct biological analog. Under dense confinement to an oil-water interface, microtubule bundles undergo a spontaneous transition to an aligned state. Soft matter physics describes such materials as liquid crystals, which are the materials used to make liquid crystal displays (LCDs). These active liquid crystals show a rich variety of dynamical behavior that is totally inaccessible to their equilibrium analogs and opens an avenue for studying an entirely new class of materials with highly desirable properties.

Lastly, inspired by streaming flows that occur in cells, the researchers encapsulate the bundled active networks into spherical emulsion droplets. Within the droplet, microtubules again formed a self-organized nematic liquid crystal at the oil-water interface. When the droplets were partially squished between glass plates, the streaming flows generated by the dynamic liquid crystals lead to the emergence of spontaneous self-motility.

This research constitutes several important advances in the studies of the cytoskeleton, non-equilibrium statistical mechanics, soft-condensed matter, active matter, and the hydrodynamics of fluid mixing. The researchers have demonstrated the use of biological materials to produce biomimetic functions ranging from self-motility to spontaneous fluid flows using fundamentally new mechanisms. Additionally, the experimental system of bundled active microtubules is poised to be a model for exploring the physics of gels, liquid crystals, and emulsions under far-from-equilibrium conditions.

To see more videos from the Dogic lab at Brandeis University, check out their YouTube page.

Summer course on building a microscope from simple components

This past June the MRSEC Center offered a condensed summer course based on the popular graduate course QB120: Quantitative Biology Instrumentation Laboratory.

Professor Dogic

The course was taught by Zvonimir Dogic of the Physics Department (pictured).   Prof. Dogic has extensive experience with several forms of microscopy and his Lab features several home-built or heavily modified optical setups.

The course is designed to offer students hands on experience with building their own optical setups from basic components as well as learning how to optimally acquire imaging data from commercial microscopes.  The focus was on understanding the physics behind microscope function and leveraging that knowledge towards improving data acquisition in the lab.

Initially, students used basic lenses, apertures, an objective, a camera and a light source to build the simplest possible light microscope.  This initial setup was quickly extended to include Köhler illumination, a core principle in microscopy which allows even illumination of the sample as well as access to the conjugate image plane for image filtering.

The next project required students to build a fluorescence microscope, a highly relevant and ubiquitous technique in biological imaging.  To image a slide with fluorescently labeled beads students used a dichroic mirror to separate excitation light at one wavelength from emission light at another wavelength.  A schematic diagram, a photo of this setup with the light path superimposed and actual data acquired with one of these microscopes can be seen in the video below.

Next, a more advanced technique in microscopy, total internal reflection microscopy (TIRF), was introduced and an imaging setup using this technique was built.  TIRF microscopes excel at imaging small molecules that are immobilized in a small area.  A laser beam was pointed to shine through a prism at an angle sufficient to cause total internal reflection and the resulting evanescent wave caused fluorescent excitation of the sample.  The video below shows a schematic and imaging data of a TIRF microscope built by students.

Finally, students used commercial microscopes to understand the principles behind phase contrast and difference interference contrast microscopy, both techniques well suited for imaging samples that are nearly transparent.

Overall the Course provided an excellent introduction to the physical principles behind microscope function.  I highly recommend it to anyone interested in using microscopes in their research!

MRSEC summer course in Optical Microscopy (June 20-24, 2011)

Optical microscopy has become a powerful experimental tool capable of simultaneously visualizing large scale structures such as entire cells, and fluorescently labeled single molecules within these complex structures. It has found important applications in diverse scientific fields.  The Brandeis Materials Science Research and Enginering Center will offer a one-week intense summer course in optical microscopy from June 20 – June 24, 2011, “Introduction to Optical Microscopy.“  The primary goal of the course is to train students in the fundamentals of microscopy and optics. The students will start by constructing a bright field and fluorescence microscope from simple optical components before learning how to use research grade optical microscopes. After completing the course, students will acquire knowledge necessary for using optical microscopes at limits of their capabilities and critically evaluating their performance.

This summer course is a condensed version of a popular graduate level course in  Quantitative Biology (Quantitative Biology Instrumentation Laboratory QB 120 b).  Our goal is to make this course accessible to students with all scientific backgrounds.  The course will be taught by Zvonimir Dogic, who is a faculty member in the Physics Department at Brandeis University.

More information and application procedures are available at the following website: http://www.brandeis.edu/mrsec/summercourses.html.

The Volen Center for Complex Systems Retreat, 2011

(co-written by Tilman Kispersky)

Introduction and Location

The annual Volen Center Retreat was held this week at the bucolic Warren Conference Center and Retreat in Ashland, Massachusetts.  The purpose of the one-day retreat is to provide a forum for conversation and encourage collaborations between members of the Brandeis and Volen center research communities.   Funded by the M.R. Bauer Foundation, the retreat features a distinguished invited speaker, lectures from Volen faculty that highlight the diversity of Neuroscience research at the Center and a poster session covering ongoing research projects of the members of the community.

The director of the Volen Center, Prof. Arthur Wingfield began the proceedings with a brief history of the retreat which is in its 17th consecutive year.  While historically the most common location for the retreat has been the Marine Biological Labs in Woods Hole, MA the retreat was held at the 220 acre property of the Warren Conference Center outside of Framingham this year.  Prof. Wingfield introduced the theme of the retreat: “Imaging: Recent breakthroughs in visualization – from synapses to circuits”.  Each lecture focused on data collected with advanced imaging techniques and highlighted how advanced optical methods had enabled a deeper understand of nervous system.


The first lecture was given by Prof. Aniruddha Das from the Columbia University Department of Neuroscience.  Prof. Das’ research group developed a method to perform dual-wavelength imaging to measure both the volume of blood present in a given region of cortex as well as the oxygenation level of that blood, two quantities that are combined in traditional fMRI imaging.  Using dual-wavelength imaging Prof. Das found a task-related anticipatory haemodynamic signal in the visual cortex of awake monkeys.  This signal was unrelated to either single unit activity or any visual stimulation.  The finding suggests that cortical circuits increase their blood oxygenation level prior to the expected onset of a task in anticipation of the increased computational load.

The second speaker was Brandeis Professor Stephen Van Hooser.   Prof. Van Hooser studies motion detection in the visual system and is specifically interested in how motion selectivity develops and what role sensory inputs play in this process.  The ferret visual system, the animal model used by Prof. Van Hooser, develops orientation selectivity prior to receiving any sensory input.  However, motion selectivity requires visual inputs and thus develops later, after young ferrets open their eyes.  Prof. Van Hooser presented experimental results that employed two-photon imaging to simultaneously measure the activation of hundreds of cells at depths of up to 300 um beneath the cortical surface.  By presenting moving visual stimuli Prof. Van Hooser was able to track the emergence of motion selectivity in cortical neurons and was able to influence the course of development by changing the direction of motion of the stimulus.

Following the mid-day poster session, the afternoon portion of the retreat featured a trio of talks covering some of the cutting-edge imaging work currently being done at Brandeis.  First up was Dr. Avital Rodal (pictured at right), whose lab employs an innovative, high speed confocal microscopy technique to capture high-resolution images of tagged endosomes on the move in developing fly neurons.  By combining different markers in the same experiment, Dr. Rodal has been able to demonstrate transient interactions, undetectable by traditional methods.  Potentially, her work could help us understand a range of health issues in which endosomal trafficking has been implicated, including neurodegenerative disease and mental retardation.  See the moving endosomes for yourself in a recent blog post covering her exciting work!

The next speaker was able to remind us that sometimes it takes more than biologists to do biology — especially when the task is high-throughput image analysis.  Dr. Pengyu Hong, an Assistant Professor of Computer Science here at Brandeis, shared some of his work using High Content Screening, an automated method of analyzing image data and extracting information about cellular phenotypes and neurite length from images of cell cultures.  Using data provided by his collaborators around the world, his method is able to quantify neuronal morphology, allowing for high throughput genetic and drug discovery screening at improved levels of accuracy — a previously intractable task.

The final speaker of the retreat shared with us an intriguing work in progress.  Dr. David DeRosier (pictured at left), Brandeis Emeritus Professor of Biology, currently a member of the Turrigiano lab, has been developing an imaging technique called “Cryo-PALM”. If it sounds cool, it’s much more than that; it involves holding a biological sample frozen at no more than -140C, while imaging it with a room temperature microscope objective less than a millimeter away.  It sounds difficult — and as David told us, it is! — but the potential is huge.  Dr. DeRosier hopes to be able to precisely localize fluorescently labeled proteins in the synapse down to sub-nanometer resolution, and provide the most detailed picture ever of synaptic structure.

This year’s Volen center retreat was another success, with lots of informative talks, informal mingling, and even delicious food!

Signals on the move

A hallmark feature of eukaryotic cells is their intricate subcellular membrane compartmentalization, which biochemically and spatially isolates cellular processes including signal transduction, protein synthesis, and energy production. Membrane-spanning proteins such as growth factor receptors are transported through these compartments by the actions of a host of membrane binding proteins that bend, pinch and move bits of cargo-containing membrane from one compartment to another. Growth factor receptors change their signaling properties as they transit through these different compartments, and so cells can turn growth factor signaling up or down by regulating the rate of transit. The challenge is to understand how networks of hundreds of interacting membrane deforming proteins work to control cargo traffic, and how these proteins might themselves be regulated by the cell to reroute cargo.

Live imaging of dynamic interactions between subcellular compartments in fly neurons.
(click to watch movie)

Now, in a recent study published in the Journal of Cell Biology, new Biology faculty member Avital Rodal, together with Troy Littleton at MIT, identify a novel interaction between two membrane-binding proteins, Nervous Wreck (Nwk) and Sorting Nexin 16 (SNX16), that are critical for controlling the traffic of growth factor receptors that drive the expansion of neuronal arbors. Using the neurons that innervate muscles in fruit fly larvae as a model, Rodal and colleagues show that a physical association between these two proteins is necessary to turn off signaling by receptors that have been previously activated by growth factors. Perplexingly, though Nwk and SNX16 must physically interact to execute their role in driving membrane movements, they appear to reside in different subcellular compartments, in different locations within the neuron. To solve this conundrum, Rodal and colleagues took advantage of the spinning disk confocal microscope in the Brandeis Correlative Light and Electron Microscopy facility to look at the dynamic behavior of these compartments in living neurons in larvae. They found that the two distinct compartments inhabited by Nwk and SNX16 undergo dynamic and transient interactions, which represent the point in space and time that signaling receptor cargo is transferred between compartments. These receptor trafficking events are implicated in diseases ranging from neurodegenerative disease to mental retardation and addiction, underlining the health importance of understanding how signal transduction is modulated by intracellular membrane traffic in neurons.

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