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What We Are Doing About: Nanoscience

Tiny dimensions, great expectations. That’s nanoscience in a nutshell
What We Are Doing About: Nanoscience

Peering into nature’s secrets

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Cells vary in length. Bacteria are about 1 micron long, while plant and animal cells vary from about 50 microns to meters in the case of certain neurons.
 
The cell - the elementary unit of life - is rich in engineering know-how. The ultimate self-assembler, it applies its molecular machinery to convert readily available materials from food and water into a wonderland of materials - from over 100,000 proteins, lipids and sugars, to the materials they build: wood, bones, horns, scales and skin. It performs these feats in a tiny setting. Cells are generally only a few micrometers long, and their functional units, the organelles, are only a few nanometers. Scientists around the world are hard at work applying a range of tools to chip away at the cell’s secrets by viewing and manipulating nanoscale objects within and around the cell.
 
Lessons from the cell, they believe, might prove vital in understanding the basic mechanisms of life - the key to unprecedented medical advances. The cell might also help in shaping our material world, with its varied nanostructures serving up solutions to central challenges in material design.
 
 


Connect the dots

 
Cell adhesion, in which cells bind to adjacent cells or to the matrix between them, is an essential first step in many fundamental life processes, including the formation of tissues and organs, wound healing and the exchange of information between cells, known as signaling. But how are these contacts formed and regulated? What cues within a living organism influence adhesion properties, instructing a cell to stick, move, proliferate or die?
 
Until recently, scientists studying the forces influencing cell adhesion faced a major difficulty: they lacked the tools to effectively identify and measure the minuscule forces applied between cells and their environment. Heading a multidisciplinary team, Prof. Benjamin Geiger of the Institute’s Molecular Cell Biology Department developed a powerful new tool for studying cellular adhesion, which allows the measurement of forces in the Lilliputian range of nanonewtons (one nanonewton is roughly equivalent to the weight of one thousand red blood cells).
 
The method involves creating a transparent elastic template imprinted with a grid of dots or lines spaced at fixed intervals. When a cell sticks to the patterned template and applies a force, it distorts the grid. By measuring these distortions, the scientists are able to infer the magnitude and direction of the forces applied by the cell to the contact area. This approach is proving vital in revealing the interplay between adhesion and internal cellular processes.
 
In related research, Geiger and Prof. Alexander Bershadsky of the Molecular Cell Biology Department have shown that cells constantly “probe” their surrounding by touching and pulling at it. New research questions include the nature of the forces occurring between two cells as they anchor on the same substrate, a topic that plays a role in how cells aggregate to make a tissue and may thus have relevance to tissue engineering.
 
 


Simulating life

 
In related research, Prof. Benjamin Geiger is working to construct models that simulate the conditions experienced by cells as they move around the body. In their travels, cells encounter continuously changing “terrains” determined by the type of tissue they meet. They are able to sense the chemistry, geometry and mechanical properties of these environments and to modify their behavior accordingly - for instance, applying extra adhesive force in settings lacking sufficient anchorage.
 
Collaborating with Prof. Lia Addadi of the Institute’s Structural Biology Department, Ph.D. student Baruch Zimmerman and Prof. Yoachim Spatz of Germany’s Heidelberg University, Geiger is creating artificial micro- and nanoscale models that simulate the body’s varying tissue matrices (collagen, fibers etc.) to obtain a better understanding of the interactions between a cell and its environment - specifically, how a cell’s behavior and motility are affected by the chemistry and mechanical properties of its environment. Insights into these questions may have implications in cancer research aimed at preventing the migration of cancerous cells to form metastases. The artificial models tested at the WIS may also advance tissue engineering research, yielding knowledge of the type of scaffolds needed to create specific tissues.
 
 


Soft matter science

 
When physicist Sam Safran started work in the 1980s at the Exxon petrochemical company, he had little idea this job would end up changing the course of his career, sparking an interest in the science of soft matter. Today, this field has relevance for diverse applications, from the management of oil spills to pharmaceuticals.
Also known as complex fluids, soft matter often deals with the dispersion of a solid or liquid in another liquid. In his work at Exxon, Safran, today a professor in the Institute’s Department of Materials and Interfaces, focused on unique “split-personality-like” molecules used in oil extraction and recovery. Known as amphiphiles, these molecules have both polar (charged) and nonpolar regions. While one end is attracted to polar molecules such as water, the other end is generally a nonpolar hydrocarbon chain, attracted to oils or lipids. This enables amphiphilic molecules to break up oil slicks into small droplets, which might then be further degraded by oil-eating microbes.
 
The unique polar/nonpolar duality of amphiphiles makes them key players in the body, where they self- assemble into an extremely rich assortment of soft matter structures that perform regulatory and housekeeping chores. For instance, the membranes of all cells in the body contain a nonpolar region facing the inside of the cell and a polar region on its surface, which is vital to the cell’s interaction with nearby molecules. Another example is that of micelles - a cluster of molecules critical to efficient digestion, which break up otherwise insoluble fat molecules.
 
A better understanding of the body’s self-assembling systems may help in creating vesicles for use as potent drug delivery systems.
 
 


Soft materials and cancer diagnosis

 
As a red blood cell rushes through the arteries it is repeatedly pounded, stretched and deformed as it passes small capillaries, yet it rarely breaks apart. This feat is made possible by the fact that, like all soft materials, cell membranes are relatively durable in their response to external forces.
 
Hoping to explore the relationship between cell function and the cytoskeleton (a structure just below the cell membrane that affects cell shape, division and adhesion) Prof. Safran and colleagues demonstrated that exposing live cells to a drug called latrunculin weakens the cytoskeleton, impairing its incorporation of the actin protein.
This finding may lead to new tools for cancer diagnosis and drug development. When exposed to actin-impairing drugs, cancerous cells are strongly affected since their cytoskeleton is weak to begin with, whereas healthy cells are generally better able to maintain the integrity of their cytoskeleton.
 
 


Opening the gates

 
In biblical times, the gate was the most vulnerable point of a walled city. Judges were placed there to interview travelers, verifying that their presence was welcome. The same is true of the gates to the cell’s inner sanctum - the nucleus.
 
These gates (called nuclear pore complexes) lead to and from the cell’s genetic material, safeguarding the essential codes of life. Only “desirable” molecules can pass through. Molecules that succeed in entering the nucleus from other parts of the cell activate genes, causing the information these genes encode to be dispatched to the cell’s “protein factory” by another molecule - messenger RNA - which exits the nucleus through the same gates.
 
Understanding the mechanism by which molecules pass the nucleus’ gates is crucial to controlling such traffic. These methods may be applicable in barring the entry of viruses into the cell’s nucleus, or in gene therapy, in which a beneficial gene is introduced into the patient’s DNA to replace a damaged counterpart gene.
 
Dr. Michael Elbaum of the Weizmann Institute’s Material and Interfaces Department is studying the passage of DNA molecules through these gates using optical and electron microscopy. His team applies a tool based on tiny tweezers composed of laser beams focused in a microscope.
 
In collaborative research with Prof. Alexander Bershadsky of the Molecular Cell Biology department, Elbaum and his team applied similar optical tweezers to probe cell adhesion and its relation to cell movement in the body - phenomena playing a key role in embryonic development, wound healing and other fundamental life processes.
The team designed small beads coated with proteins involved in adhesion. They then used the optical tweezers to hold the beads over the cell surface and map their resulting interaction with the cell. In the study, published in Biophysical Journal, they showed striking differences in the way different regions of the cell surface respond to the stimuli generated by the adhesion proteins, making it possible to pinpoint specific regions where adhesion takes place.
 
 


Skeletal surveying tool

 
In more materials-oriented research, Elbaum and his team are currently studying a central ingredient of the cell’s internal skeleton, known as microtubules, which might hold clues to longstanding questions in physics and biology.
 
Twenty-five nanometers in diameter and up to a hundred microns in length, microtubules are shaped as hollow, rigid, chimney-like structures. The cell uses microtubules for communication and delivery, sending “packages” running along them, driven by specialized motor proteins.
 
Studies of this system are shedding light on molecular traffic in the cell. Since microtubules are elastic polymers, such studies may also yield a better understanding of the dynamics of both natural and synthetic polymers, revealing properties important to a range of applications, from food packaging to industrial glues.
 
 


Metal ‘a day to keep diseases away

 
Every time we breathe, the oxygen drawn into our lungs binds to iron atoms present in hemoglobin molecules in the blood. The hemoglobin transports the oxygen to cells throughout the body, where it is released and used to produce energy. Iron’s ability to bind, release and activate oxygen stems from its capacity to “give” and “receive” electrons. In this respect, it is similar to other metals such as copper, cobalt and nickel. These metals underlie the actions of numerous enzymes - “molecular machines” essential for nearly all cellular processes.
 
Prof. Daniella Goldfarb, of Institute’s Chemical Physics Department, is studying metalloenzymes (enzymes containing iron and other metals) with the aim of mapping the precise structure of their metal-containing active sites. Insights in this field will help advance the construction of molecular machines - 10 to 50 nanometers large - that, equipped with these metal-containing active sites, would be capable of performing diverse industrial functions, some dramatically improved from existing technologies.
 
A good example is that of ammonia production - a reaction that calls for extreme temperatures and pressure when performed industrially, yet is synthesized in bacteria in a series of elegant biochemical reactions, at ambient temperatures and without the production of harmful byproducts.
 
Mapping the metal-containing sites may also lead to methods for repairing damaged enzymes, offering an invaluable medical tool since damaged or faulty enzymes lie at the root of many diseases.
 
 


First sightings of individual proteins as they fold

 
Proteins, the fundamental components of all living cells, start out as randomly shaped chains and twist into a well-defined structure that determines their function. A botched job of protein folding has been linked to a growing list of diseases, including Alzheimer's and certain cancers.
 
Until recently, scientists studying protein folding had to rely on information gathered from a huge number of molecules. The experimental results represented an average of the different processes these molecules underwent and could not pick up individual differences. This shortcoming highlighted the need for a new technology that would make possible the study of individual proteins as they fold - a huge challenge since proteins are generally only a few nanometers in size and are constantly on the go.
 
Applying a new optical technology designed in his lab, Dr. Gilad Haran of the Institute’s Chemical Physics Department has made the first glimpses ever of single proteins in the process of folding. The technology’s success lies in striking the right balance. Since proteins are continuously active, one must limit their motion to get a clear understanding of their folding process. However, a fully immobilized protein defeats the purpose. It won’t fold. Earlier attempts to gain a steady look at proteins sought to pin them down to a surface; but this could be achieved only by binding the protein to a surface, thus changing its properties.
 
To skirt this obstacle, Haran’s team designed novel vesicles that envelop the proteins in question. Each vesicle is 100 nanometers wide and designed to envelop a single protein molecule, generally only 3-4 nanometers long. Unaware of their scientist-made borders, the proteins can move about freely, yet not so actively as to impair the scientists’ ability to observe their behavior.
 
The results verify what theoretical scientists have suspected for nearly a decade - that proteins may vary in their folding process. Even identical proteins ending up with the same shape may take different routes to reach it. The new WIS technology might help clarify the reasons for protein misfolding and ensuing disease.
 
 


DNA? Proteins? Fish ‘em out with a nanoprobe

 
Coupling the delicate touch of a nanotube probe with atomic force microscopy (AFM), Dr. Ernesto Joselevich is able to produce today’s highest-resolution images of live, moving DNA.
 
AFM works like a record player “reading” surfaces with a needle-fine tip; it rises and descends as it meets “bumps” or “valleys” in the target surface. These motions are translated via a computer to create an atomic-scale image. But while AFM provides detailed topographical information, it offers only limited information about an object’s surface chemistry. “It’s like being able to determine where a cake is without knowing whether it’s a chocolate swirl or blueberry with cream,” says Joselevich, of the Institute’s Materials and Interfaces Department.
 
Seeking to enhance the tool’s sensitivity, Joselevich, at the time completing a post-doc at Harvard under Prof. Charles Leiber, decided to link it up with nano-tubes that were one to a few nanometers in diameter. The idea was to replace the conventional AFM probe with nanotubes fitted with different chemical tips, such as molecules that might interact with those on the target surface. By detecting binding forces between these chemical tips and the target surface, he reasoned, one might gain new information about the surface chemistry.
 
Another motivation was the nanotube’s tiny diameter. The team hypothesized that they could significantly increase AFM resolution by replacing its standard tip, which has a radius of curvature of 5 to 20 nanometers, with that of a carbon nanotube 0.5 nanometers in radius. “A blunt tip makes it difficult to detect fine objects. It’s like trying to feel or pick up a grain of rice with a boxing glove,” explains Joselevich.
 
The study, published in Nature, showed that he was on the mark. The new approach successfully detects the presence of specific molecules on the target surface. Likewise, having added a temporal resolution system that photographed the interaction every 30 seconds, Joselevich is able to view live, moving DNA as it undergoes various biochemical processes. This real-time view offers an important advantage over electron microscopy, which can be applied only to dead samples, since the high flow of electrons intrinsic to that technology destroys the sample.
 
Potential future applications of chemical force microscopy range from basic research aimed at a better understanding of gene expression, to the ability to detect a person’s susceptibility to disease, to industrial applications, including the detection of chemical impurities on semiconductor chips.

 

 

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