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Bioimaging conference

The conference "Methods and Problems in Bioimaging" was held on June 24, 2019 at the weizmann Institute campus. The event brought together computer scientists and biologists, that encounter challenges in the field of bioimaging. 

Participants presented their data and algorithms, discussing topics such as detection, segmentation, classification, matching, registration, and reconstruction. 


Zebrafish imaging and cancer

One Weizmann Institute scientist is making critical advances in studying the lymphatic system, a mechanism involved in the metastatic spread of cancer cells, by conducting live imaging experiments in zebrafish embryos.

Prof. Karina Yaniv, along with her team members in the Department of Biological Regulation, have long focused on uncovering the origins of lymphatic vessels during embryonic development.

After discovering that the body has a special store of stem cells that give rise to these vessels, the scientists began growing lymphatic cells in culture for the first time. The new research not only solved a century-old disagreement about the origin of the lymphatic system, but also provided therapeutic avenues for the treatment of lymph-related pathologies.

The team then moved on to exploring what exactly the lymphatic cells do, and how they do it. They performed live imaging experiments in zebrafish embryos, tracing the differentiation and migration of previously identified stem cells. The scientists were able to clarify key differences between those stem cells that generate adult lymph cells and others that give rise to the vasculature of the digestive system. These findings, according to Yaniv, may shed light on the mystery of where cancerous blood and lymphatic cells originate. With suspicions that adult stem cells could be the source, the scientists are now tracking the stem cell population of adult zebrafish. 

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The way proteins gossip

Just like office employees often congregate to “gossip around the coffee machine”, so do many proteins. According to the findings of Dr. Emmanuel Levy from the Department of Structural Biology, proteins often interact “promiscuously” with one another.

During his postdoctoral work at the University of Montreal, Dr. Levy showed how key proteins alter their chemical properties to minimize their promiscuous interactions.  Now, Dr. Levy is devising new ways to understand how promiscuous interactions evolve. Ultimately, he hopes to better understand how proteins are organized within cells, and use this knowledge to treat cells in diseased states.

In his lab at the Weizmann Institute, Dr. Levy will be using a spinning disk microscope as a platform to visualize fluorescently tagged proteins in baker’s yeast, a perfect model organism to study cellular biophysics.

This approach will allow his team to acquire images of cells at both high-throughput and high resolution, with high-speed, and using a variety of fluorescent channels. The technical infrastructure for these experiments involves a dual camera setup coupled to LED illumination to avoid moving parts, and a hardware focus—collectively coupled to a liquid handler and automated incubator through a robotic arm loader. 

Image (left): Protein surfaces are commonly assumed to be naturally soluble and non-sticky, so that only specific protein-protein interactions are made. This is illustrated by the protein model on the right, covered with spikes. However, we show here that in their default state, most proteins have a consistent propensity to stick to other proteins, as illustrated by the left protein model covered with honey.

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Light on brain chemistry

Using an innovative method to switch the electrical impulses of brain cells on and off with pulses of light, Weizmann Institute scientists are now obtaining reliable structural and spectroscopy data from mouse brain tissue. The new, experimental protocol relies on optogenetics, a genetic engineering technology that can control the brain with light. 

Dr. Assaf Tal, from the Department of Chemical Physics, and Dr. Ofer Yizhar, from the Department of Neurobiology, combined their expertise to develop a method based on magnetic resonance spectroscopy, which makes it possible to visualize how the brain’s neurochemical profile changes in response to selective optogenetic light pulses. While the scientists began by working with computer simulations, they are now planning to conduct similar studies on live mice, in order to determine how the chemistry of the brain transforms in real time.

Concurrently, the Weizmann Institute recently installed an ultra-high field 15.2 Tesla magnetic resonance imaging scanner for preclinical research in animal model systems. Dr. Tal and Dr. Yizhar’s preliminary assessments strongly support the use of this scanner for their continued research. They are in the process of translating their work for use with the new machine, after which they will begin studying brain chemistry changes in live mice. 

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Single-celled architects

In nearly every ecological niche across the Earth, single-celled algae, called diatoms, are hard at work crafting elaborate cell walls at a nanometer scale. As they produce exceedingly thin layers of silica - a material similar to common glass - diatoms are building walls through methods unrivaled by any human technique. While the potential biotechnological applications for such a mechanism are plentiful, scientists have struggled to mimic the process due to the insolubility and short-lived nature of the inorganic materials involved.

Aiming to overcome these obstacles, Dr. Assaf Gal, from the Department of Plant and Environmental Sciences, has joined forces with Dr. Omer Yaffe, from the Department of Materials and Interfaces, to employ a state-of-the-art, customized spectroscopy technique. The scientists are using a Raman spectrometer, which has the unprecedented ability to zero-in on single, isolated cells and detect low-frequency motion.

With their newfound ability to witness silica formation firsthand, Dr. Gal and Dr. Yaffe are working to discern the different stages of mineral formation as it occurs within the cell. By shedding light on how diatoms could produce such magnificent mineral material, Raman spectroscopy could pave the way for groundbreaking insights into an obscure but powerful biological process. 

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Neuroimaging and artificial networks

While the in-vivo imaging of cerebral vasculature has long been vital to medical scientists, the expensive, invasive nature of existing technologies has hampered the advancement of brain studies. 

Dr. Vyacheslav Kalchenko is working to change this reality. Together with his colleagues at the In Vivo Optical Imaging Unit, he has successfully developed a simple approach that utilizes standard fluorescent imaging protocol, inexpensive micro imaging, and computation procedures to provide a clear and accessible picture of the brain’s vascular network.

Preliminary results have shown an ability to clearly visualize the middle cerebral artery and other major vessels of the network, as well as elucidate the measurements and dynamics of blood flow.

Aiming to improve the penetration depth and resolution of his methodology, Dr. Kalchenko will next begin making use of an Artificial Neural Network (ANN) and relevant computer hardware. Doing so will create a smart imaging approach that could potentially have an enormous impact on the field of neuroimaging, while significantly expanding the capabilities of preclinical functional studies of the brain. 

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The first line of defense against invaders

Certain cytokines – the proteins responsible for conveying signals into the cell from the external environmental – play a critical role as protectors against foreign invaders. After a cytokine binds to the portion of a receptor protein located outside the cell, a signal is transferred inside for further processing. Particularly of interest to scientists is the potential to obtain a variable set of outcomes from the same cytokine, depending on the biophysical and cellular parameters of receptor activation.

For years, Prof. Gideon Schreiber, from the Department of Molecular Sciences, and Prof. Abraham Minsky, from the Department of Structural Biology, have been jointly investigating structural and functional aspects of the type I interferon system (IFN) – a cytokine that is the first line of defense against viruses and other pathogens. While the scientists have established how various modes of binding by IFN trigger different signals, their understanding as to how the extracellular signal is translated in intracellular activation is much less clear.

To this end, Prof. Schreiber and Prof. Minsky are studying the structures of the intracellular domains of interferon receptors together with different effector proteins. Structural analysis of this interaction is made possible through single particle cryo-electron microscopy, using a direct detector that provides a much better signal-to-noise ratio than previous methods. 

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Tracking migration of white blood cells

Equipped with a state-of-the-art, live imaging fluorescent microscope, Prof. Ronen Alon is tracking the differences in migration routes of white blood cells (leukocytes), as they travel from the bloodstream to specific inflammation sites. Visualizing these routes, and the complex mechanisms governing them, may offer vital information as to why leukocyte response to a variety of medical conditions can sometimes be weakened.

While scientists know that chemokine molecules, expressed on endothelial cells in blood vessel walls, mediate the weakening of leukocyte response, they are still working to elucidate the processes behind this dynamic. The attenuation of such molecules has already been shown to reduce white blood cell recruitment in numerous pathological and therapeutic settings, such as allergy, infection, chronic inflammation, myocardial injury, atherosclerosis and bone marrow transplant. A deeper understanding of how these vascular molecules function in recruiting immune cells from the blood to specific tissues is, therefore, of enormous importance.

Prof. Alon and his lab members from the Department of Immunology are now working with their new inverted IX83 Olympus wide-field fluorescence microscope, which has a motorized stage and high resolution. Using this system and its accompanying software packages, the researchers have already identified major variations in the routes taken by different types of immune cells, as they cross through monolayers of inflamed endothelial cells. Their findings may have an impact on the understanding of how specific pathogenic leukocytes cross specialized types of inflamed vessels that are typically impermeable to most other immune cells. 

Image (left): Barzili, S. et al/Journal of Leukocyte Biology, vol. 99 no. 6 1045-1055, June 2016

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Looking at neuronal connectivity

As the human brain processes sensory information, coordinates motor activity, and stores and retrieves memories, a large number of molecules are working in concert to fine-tune the activity of the individual neurons that govern circuit connectivity.

A slight change in the function of one of these molecules, however, could lead to devastating consequences such as uncontrolled electrical activity in the case of epilepsy or neuronal death in conditions like Parkinson’s or Alzheimer’s diseases. If this change occurs in the early stages of development, other harmful possible outcomes include mental retardation or autism.

Prof. Eitan Reuveny, from the Department of Biomolecular Sciences, is building a multi-photon microscope that will help researchers understand this complex system, by enabling the study of neuron-neuron connections—a crucial element in brain function in both healthy and diseased circumstances.

The multi-photon microscope, supported by the Krenter Institute, employs very strong and fast light pulses that allow the scientist to see deep into neuronal tissues and monitor neuronal communications and activities under native environments. By implementing this state-of-the-art tool, Prof. Reuveny hopes to take groundbreaking steps toward deciphering neuronal connectivity. 

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Cell invasion and cancer metastasis

Living cells display an extraordinary capacity to sense the chemical and physical properties of the extracellular environment, and respond to environmental cues by altering their fate and behavior. Behind these interactions - particularly the adhesion of living cells to one and other, and to their surrounding environment - are a number of complex molecular mechanisms that likely contribute to the spread of cancer.

Prof. Benjamin Geiger from the Department of Molecular Cell Biology is investigating the role of cell-matrix and cell-cell adhesions in regulating collective cell migration. 

This topic appears to be highly relevant to cancer metastasis, a process through which individual cells or small cell clusters are dislodged from the primary tumor, invade nearby blood and lymphatic vessels, and are carried to distant tissues - most commonly in the lungs, liver, or brain - where they form secondary tumors. It has been shown that collective cancer cell invasion increases the cancer’s ability to survive the metastatic process.

With the support of the Krenter Institute, Prof. Geiger has been able to study a novel form of collective migration, manifested in the highly metastatic 4T1 breast carcinoma cell line. These cells are considered to be an excellent model for metastatic cancer. Thus far, he has found that these cells migrate collectively even while maintaining long-distance tethers interconnecting them.

Prof. Geiger and his team are exploring the mechanisms of tether formation, their mechanical properties like strength and elasticity, the mechanism underlying their ability to harness migrating cells, and the cues the tethers transmit to neighboring cells to induce cell convergence. The characterization of this migratory mechanism may facilitate the development of reagents that will specifically interfere with this massive migration, and potentially reduce or block the dissemination of tumor metastases. 

Image (left): van Roosmalen, W et al/Journal of Clinical Investigation, 125 (4):1648-1664.

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Metals and cancer growth

While modern electron microscopy excels in visualizing cell structure, it is very poor in distinguishing the molecular or atomic makeup of cellular components. Proteins, sugars, and lipids consist primarily of carbon, nitrogen, oxygen, and hydrogen in different proportions, but the process of image formation reduces this information to levels of gray.

​Many essential enzymatic processes depend on heavier metal ions such as zinc, calcium, or even iron. Conventional imaging cannot reveal these, while the tools that exist for atomic analysis require high doses of electron radiation that damage the delicate biological materials.

This past year, Prof. Irit Sagi from the Department of Biological Regulation and Prof. Michael Elbaum from the Department of Materials & Interfaces have been employing an old-new method for the 3D tomography of cells, and potentially even of tissues. Rather than illuminating a field of view on the sample, like a light microscope, they scan a focused beam of electrons across it, like an old cathode-ray tube television. The specimen scatters the incoming electrons, which are simply collected on the opposite side. Known as “scanning transmission electron microscopy” (STEM), this was actually the mode of operation for the very first electron microscope. It was abandoned until 1970, and lately has become very popular in the material sciences yet largely ignored in the life sciences.

Profs. Sagi and Elbaum were able to demonstrate the advantages of STEM, particularly with regards to imaging lighter elements—like carbon, nitrogen, and oxygen—that make up the molecules of living matter. Yet perhaps more intriguingly, the scientists have been able to use the old-new method to tune the imaging conditions to optimize sensitivity for lighter or heavier elements. The two research groups decided to work together to try to reveal the metal ions that catalyze the degradation of extracellular tissue matrix proteins such as collagen. This is a challenging enterprise with enormous implications for the prevention and therapy of cancer, as cancerous cells must break down this matrix that holds the original tissue together.

The project involves the study by STEM of a variety of samples that feature zinc-based enzymes secreted by cancer cells, as part of the attack on the collagen matrix. The project's goal is to distinguish the zinc through its distinct electron scattering pattern, and thereby to detect the distribution and activity of these enzymes in cancer metastasis. 


Image (left): shimshoni et al/Gut 64 (3).

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A multi-channel recording

In order to get a clearer picture of the formation of blood and lymphatic vessels during embryogenesis, Dr. Karina Yaniv, from the Department of Biological Regulation, is taking advantage of the genetic accessibility of zebrafish embryos.

Because these embryos develop externally, they provide a noninvasive opportunity to observe stage-by-stage development of the entire vascular system. To do so, Dr. Yaniv and her team rely on their ability to image live embryos at high-resolution, through sophisticated technology.

The Krenter Institute has supported the purchase of a Zeiss LSM 700 laser scanning confocal microscope, equipped with a manual XY-stage, three dye filter sets, as well as dry and water-dipping objectives. It features two confocal detectors, and three solid-state lasers with varying intensities.

The system allows for multi-channel recording of reflection, fluorescence, and transmission images, as well as a variety of other applications. Among these functions are photo-activation and photo-bleaching experiments with freely definable regions of interest; fast image acquisition for live cell imaging and time-lapse studies; Z stacks for localization of cells in living tissues; and high-resolution localization of sub-cellular compartments. 

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The mystery of neural communication

Imaging the activities of a specialized nervous system membrane called myelin could provide critical insights into the formation of certain diseases like multiple sclerosis. Of particular interest is myelination, or the process of electrically insulating axons—nerve fibers that conduct electrical impulses—to promote the rapid and energy efficient propagation of action potentials.

Within the central nervous system, myelination is performed by oligodendrocyte cells, which extend processes to extensively wrap selected nearby axons in myelinated axon tracts.

When healthy myelin is lost in demyelinating diseases such as multiple sclerosis, normal action potential propagation is disrupted. Successful myelination requires communication between oligodendrocytes and axons, but the underlying molecular basis of this communication remains largely unknown. The identification of receptors that mediate these interactions is therefore expected to provide novel targets for enhancing remyelination, neuroprotection, and repair in demyelinating diseases.

Prof. Elior Peles, from the Department of Molecular Cell Biology, is exploring how a family of proteins called G-protein coupled receptors help mediate intercellular communication and myelination in health and disease. To do so, his lab has acquired and installed a new confocal microscope, which is already adding value to their research. For example, postdoctoral fellow Dr. Hyun-Jeong Yang found that G-protein coupled receptor 37 (GPR37) regulates oligodendrocyte differentiation, myelination, and response to damage. Such findings could significantly influence the study of relevant diseases. 

Image (left): Yang HJ/Nature Communications 7:10884.

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