What we are doing about nanoscience-Nano Biology we are doi… · Having devised nanomachines...

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Nano Biology

Having devised nanomachines capable of manipulating single atoms and molecules and begun toapply these technofeats to modify the material world around us, scientists are now shifting their gazeinward, to the human body. They envision nanorobots coursing through our bodies able to fix danger-ous mutations on the spot, cleanse blood vessels or secrete insulin to counter an abnormal rise inblood sugar levels.

The quest of nanomedicine, however, has had its fair share of controversial enthusiasts, offeringgrandiose scenarios of future medical therapies. Set in motion by Richard Feynman’s 1959 lecture onminiaturization (see p. 7), it captured popular imagination and picked up speed following IsaacAsimov’s Fantastic Voyage (1966). This science fiction classic describes a crew of miniaturized humans

Roaming a molecular-scale kingdom, nanotechologies may change the face of health care

In the future, biologists will use assembler-built nanomachines toprobe and modify living cells.

Eric Drexler, Engines of Creation, 1986

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rushing to save Professor Beans, a miniaturization expert who has suffered a life-threatening bloodclot deep in his brain. The rescue team navigates through Beans’ circulatory system in an atomic-scale submarine.

Eric Drexler addressed the implications of new nano technologies in his classic “Engines of Creations“(1986). His logic was simple: “Being made of molecules… we will apply molecular machines to bio-medical technology… [these] machines will combine sensors, programs and molecular tools to exam-ine and repair the ultimate components of individual cells.”

At the time, most of his ideas were deemed far-fetched at best, but now, nearly 20 years later, proto-types of his proposed scenarios are beginning to pop up in research labs around the world. At theWeizmann Institute of Science, researchers have created a tiny computer built of DNA molecules thatdetects prostate cancer conditions in a test tube. And elsewhere in the nanoscience world, researchersare working to create soap-like films to encapsulate drugs that could deliver their medicinal cargo righton target. The films would protect the drug in the bloodstream, releasing it only under certain chemicalor thermal conditions, thus preventing wholesale release of a potentially toxic drug. Other nanotoolsmay identify the presence of bacteria and viruses, which, like many biological particles, have well-defined electrical properties and thus oscillate in characteristic ways when exposed to an electric field.

Numerous challenges remain – technical, scientific and even psychological – until nanomedicine willdirectly influence healthcare. Here’s a look at some of the early steps taken here at the Institute.

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Learning from nature

In the early 1940s, Swiss engineer Georges deMestral went for a walk in the woods with hisdog. Upon his return he noticed they were bothcovered with seeds of a burdock plant.

Removing the burs proved a frustrating task.Taking a closer look, de Mestral observed that the burs had hundreds of tiny little hooks – aclever trick for a plant wishing to disperse itsseeds. He thought this might be an ideal meansof joining two fabrics together – and the idea ofVelcro was born.

Today Velcro is found on everything from zippersto sneakers to space suits, and scientists are work-

ing on yet another form that rips apart silently – acritical ingredient for military operations.

Velcro is a classic example in the story of biomim-etics, a field that has scientists turning to nature toexamine its countless bioengineering feats, pol-ished over time. The hope is that new ideas foradvances in medicine, technology and industrymight be hidden in some of the solutions evolvedto meet the challenges of life – from bones andteeth, capable of withstanding decades of grindingwear and tear, to the enormous tensile strengthand elasticity of spider dragline silk, which ouncefor ounce is stronger than steel, enabling a dan-gling spider to safely dive down and nab its prey.

Biological materials and systems are multifunctional, adaptive, nonlinear, complex, and, in general, just "weird and wonderful.”Biologist Stephen Wainwright, Duke University

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Birds don’t have ‘em, nor do bees; sharks can replacethem almost immediately if they break; and we humanshave teeth that, excluding sugar junkies and nightgrinders, can last a lifetime given the right dental care.

A team of Institute researchers has now discovered akey factor explaining this hardiness: a spring-like structure that absorbs the mechanical stress incurred asteeth chew, grind or, as circumstance would have it,chatter their way through an arctic freeze. Interestingly,this structural feature constitutes only a tiny percentageof the overall tooth.

The team, consisting of Prof. Stephen Weiner of theStructural Biology Department and post-doc Dr. RhiziWang, began by scouring the literature in search of adental component that might fit the bill of mechanicalstress absorber. “Drawing on his materials scienceexpertise, Wang put his finger on the core question,”says Weiner. “Given that the two main components ofteeth are enamel – a hard, brittle material – and dentin,which is much softer, Wang hypothesized that theremust be an intervening layer that allows these two verydifferent materials to work together.”

The researchers knew that studies dating back to the1960s had uncovered a certain structural zone posi-tioned directly between enamel and dentin, but theyfound no follow-up studies exploring its significance.They decided to determine whether teeth actually com-press preferentially in this unexplored area when sub-jected to mechanical stress.

As published in the Journal of Biomechanics, the teamfound that the structure in question, which they dubbedthe “soft zone,” is where almost all compression takesplace. The study showed that the zone – which is mere-ly 200 microns thick, compared to enamel’s 1,000microns and dentin’s 5,000 – is in fact the “workingpart” of the tooth. When we chew, the enamel part ofour teeth is pushed back while the soft zone compress-es. It then functions like a spring, bouncing back afterthe compression.

Together with Prof. Asher Friesem and dentist PaulZaslansky, now a Ph.D. student at the Institute, theteam is currently using a new technique known asspeckle interferometry to map the deformation ofobjects in response to an applied force, at a resolutionof tens of nanometers. An enhanced understanding ofdental stress absorption mechanisms should prove valuable in tooth reconstruction.

Dealing with the daily grind

Prof. Stephen Weiner holds the Dr. Walter and Dr. TrudeBorchardt Professorial Chairin Stuctural Biology

Prof. Asher Friesem holds the Peter and Carola KleemanProfessorial Chair of OpticalSciences

Tiny sspring-like sstructure aabsorbs tthe mechanical sstress iincurred bby tteeth

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Trillions of microscopic computers vigilantly patrollingyour body in search of disease? Institute researchershave recently made a pioneering step in this direction,developing a biological computer able to identify _ in a test tube _ molecular changes indicative of certain cancers, to diagnose the type of cancer, and to react by producing an appropriate drug.

The study, recently published in Nature, was performedby Prof. Ehud Shapiro of the Departments ofComputer Sciences and Applied Mathematics andBiological Chemistry, his research students YaakovBenenson, Binyamin Gil and Uri Ben-Dor, and Dr.Rivka Adar.

The team programmed their computer to detect prostatecancer and one form of lung cancer. The computerevaluates four genes that become either under-or over-active once the disease sets in. The genes chosen con-trol the expression of messenger-RNA (which carriesinformation from the nucleus to the ribosome, the cell’sprotein factory). The scientists introduced different levels of these RNA molecules into the test tube to simulate the presence or absence of cancer.

Made entirely of biological molecules, the computerhas three components _ input, computation and output.The first consists of short strands of DNA, called transition molecules, which check for the presence ofthe messenger RNA produced by each of the four cancerous genes.

The second component is a computation (diagnostic)module, consisting of a hairpin-shaped long DNAstrand. As the computer’s input component checks forthe presence or absence of the four cancerous markers,this diagnostic unit checks each input in turn, produc-ing a positive diagnosis of malignancy only if all fourmarkers point to cancer.

This diagnostic module also contains the computer’sthird component: a single-stranded DNA that is knownto interfere with the cancer cell’s activities. In the case

of a positive diagnosis, the unit releases its hold on thetherapeutic unit, activating its cancer-fighting potential.

Shapiro’s team first went on record in 2001, when itcreated the first autonomous biological nanocomputer.Made entirely of biological molecules, the computer'sinput, output, and “software” were made up of DNAmolecules. The device was so small that as many as atrillion such computing devices could work in parallelin one drop of water, collectively performing a billionoperations per second with greater than 99.8% accuracyper operation. It was recently awarded the GuinnessWorld Record for the “smallest biological computingdevice.”

Shapiro: “Our study offers a vision of the future ofmedicine. It is clear however, that it may take decadesbefore such a system operating inside the human bodybecomes a reality.”

Biological computer diagnoses cancer _ in a test tube

Prof. Ehud Shapiro

Biological ccomputer ddiagnoses ccancer iin aa test ttube aand pproduces aappropriate ddrug

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In 1954 researchers at the Weizmann Institute builtthe first electronic computer in Israel, and one of thefirst computers worldwide, which they fondly namedWEIZAC. Thirty years later, silicon chip computersroutinely functioned at a rate that was thousandsand millions of times faster than WEIZAC.

Today, research at the Institute targets the develop-ment of ever-faster, more compact chips designed

according to the emerging principles of quantumelectronics. These will inevitably leave silicon chips in the dust, much as the silicon chips onceturned WEIZAC into a museum exhibit.

Yet even before these quantum electronic chips havebecome a reality, they already have a potential suc-cessor – the tiny biological computer developed byProf. Shapiro’s team.

Computers in the dust

c o n t i n u e d

Body joints are superbly lubricated. They have to be.As the meeting point between every two bones in our body, they are what makes our every movementpossible – from walking, bending and maneuvering our fingers to playing ball and dancing. And they’resupposed to last a lifetime.

Mimicking key design elements of this biolubricationsystem, physicist Prof. Jacob Klein of the WeizmannInstitute of Science, has recently created a syntheticlubricant that cuts friction by a thousand-fold or more.The study, published in Nature, could lead to a range ofapplications – from longer-lasting micromachines andhigher-density hard disks to biomedical devices, includ-ing improved hip transplants and treatment for dry eyesyndrome.

Previous studies had suggested that biolubrication sys-tems, including those in our joints and eyes, may con-tain hyaluronan, a molecule that coats the rubbing sur-faces of our joints, shielding them from mechanicaldamage. Hyaluronan was also known to be stronglyattracted to water. But how these two factors combinedto create the most effective lubricatory system any-where, remained a mystery.

Klein and colleagues suspected that in joints, hyaluro-nan may be attached to a thin cartilage layer coveringthe bone, while parts of this long, chain-like moleculestick out into the synovial fluid between the bones,similar to bristles on a hairbrush. These bristles or others playing a similar role, they believed, function as the body’s lubricants.

To test their theory, the team developed a syntheticmodel that mimicked a double-brush system, anchoringtwo charged molecules (polyelectrolytes) to opposite-facing ceramic surfaces. The resulting system showedextremely effective friction resistance, particularlywhen exposed to a water-based solution. “The brushesstrongly try to avoid each other, resisting penetrationeven when an external force is applied that pressesthem closer. This enables them to easily slide past oneanother,” says Klein.

The superior lubrication may largely be explained byelectrical charges. The synthetic brushes were designedto imitate the electrically-charged nature of biolubri-cants. Similar to the negative charge characterizing the hyaluronan molecule, for instance, the end of thesynthetic brushes stretching away from

The slick joint

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the ceramic surface was designed to benegatively charged. This negative charge then attractedwater molecules – which in fact explains why thebrushes performed most effectively in a water-basedsolution. “The water molecules are tightly bound tocharges on the brushes, causing them to act like molec-ular ball bearings to reduce friction,” says Klein.

Other players in this charge cast are the small mobileions trapped in the space between the bristles.According to Klein, when the brushes approach oneanother, their respective clouds of positive ions aremutually repellant, increasing the brushes “distaste” of penetrating one another.

“Our general idea was to draw on nature, says Klein.“It made sense to try out the design principles evolvedand optimized over millions of years.”

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Prof. Jacob Klein holds theHermann Mark ProfessorialChair of Polymer Physics

Mimicking nnature, aa nnew llubricant ccuts ffriction by aa tthousand-fold oor mmore. FFuture aapplicationscould iinclude iimproved hhip ttransplants

c o n t i n u e d

Two hundred and six – this is the number of bones inthe adult human skeleton. Over the years of your life,as you walk, play basketball, dance through the nightor bungee jump from a steep cliff, these bones will seeyou through, supporting your weight when you standupright and protecting your brain and internal organs.

How bones withstand the immense array of mechanicalstresses imposed upon them has long fascinated scien-tists, who have set about probing their chemical andbiological properties and even crushing them to deter-mine the relationship between their structure and theiroutstanding performance. Yet despite several decades of research, a full understanding of this complex bio-logical material remains elusive.

The beauty of bone stems from two key properties – itis a composite material and it is highly hierarchical instructure. The principle of forming a composite is to taketwo materials, often highly different from each other –say, a soft and an extremely hard material – weave themtogether somehow, and, presto, a new material is bornthat is generally far superior to either of its individualcomponents.

In bone, this partnership comes in the form of a ceramic-like, brittle mineral salt called hydroxyapatite, which isbolstered by collagen (a protein) that adds elasticity andstrength. The tissue has several levels of organization,ranging in scale from nanometers to centimeters, eachwith a different structure and function. Adding to this

Humpty-Dumpty mechanics

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complexity is the fact that bone changes over time,with specialized bone cells actively replacing olderbone tissue in a process that has adults renewing theirentire skeleton roughly every 7-10 years.

In the 1990s Prof. Stephen Weiner of the Institute’sStructural Biology Department and Prof. DanielWagner of the Materials and Interfaces Department collected data on the micro-mechanical properties ofbone and developed a mathematical model explaininghow bone’s various components affect its mechanicalfunction, including bone elasticity. The model made itpossible to predict the mechanical properties of bonewith unprecedented accuracy.

Weiner is currently working to further understand the contribution to mechanical strength made by theindividual cylinders within bone. Each of these cylin-ders changes over time, altering its mineral content and thus its mechanical properties. “While past studiessucceeded in determining the average mechanical properties of bones, what we really need to know ishow each of these individual cylinders responds tostress,” says Weiner. Insights at this structural levelmay yield new treatments for osteoporosis and otherbone diseases.

Bone sstudy ttargets iimproved osteoporosis ttreatment


Prof. Daniel Wagner holds the Livio Norzi Professorial Chair

Osteoporosis, or porous bones, is a disease characterized by structural deterioration of thebone tissue, leading to low bone mass, fragility andincreased vulnerability to fractures of the hip, spine,and wrists.

Generally appearing at age 50 or above, osteoporosis is caused by unbalanced bone “remodeling,” as cells

responsible for breaking down old bone tissue (osteoclasts) become more active than those layingdown new tissue (osteoblasts), causing bone loss.

The disease affects more than 44 million people inAmerica alone, 68 percent of whom are women,causing an estimated annual national expenditure of $17 billion.

When bones become porous

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Back when marine animals first began trying on miner-alized, exoskeleton armor, over 550 million years ago,sea urchins had a crucial “choice” to make. The oddspointed to calcite, an abundant calcium carbonate min-eral, as a natural candidate for their skeletal and spineconstruction. But while clearly the “cheapest” materialavailable, calcite seemed a fragile choice at best – it’san extremely brittle material, easily shattered bymechanical stress. Some of their contemporaries optedfor silica, magnetite or calcium phosphate. Yet seaurchins stuck with calcite. They then proceeded toevolve unique biological adaptations to dramaticallyenhance its material strength.

At the Institute, Profs. Stephen Weiner and LiaAddadi have discovered key features that explain thesurprising strength of sea urchins, as well as of mol-lusks and bones – all natural composites.

Scientists had long been unable to explain the durab-ility of sea urchin spines, which they believed consistedentirely of a single calcite (and thus highly fragile)crystal. The Weizmann scientists revealed that whilecalcite indeed constitutes 99.9 percent of the urchinspine, the remaining 0.1 percent consists of proteinsentrapped within the crystalline matrix. And amazingly,that is what makes all the difference.

Working with researchers from the Brookhaven NationalLaboratory in New York, the Weizmann team discov-ered how the entrapped proteins act to reinforce urchincalcite against fracture, preventing cracks from spread-ing through the crystal. The scientists grew pure calcitecrystals in solutions containing proteins extracted fromurchin spines. They found that the proteins integratedinto the crystal, altering its structure and making it farless brittle. The question remained, however, how acomponent present in such minuscule proportions couldhave such far-reaching effects on material quality.

Follow-up studies showed that the proteins had inte-grated into the pure crystals preferentially, along planesthat are oblique to the crystal cleavage plane, thus dis-

rupting fracture propagation. “The crystal's ability towithstand mechanical stress is enhanced because result-ing cracks do not rip catastrophically along the cleav-age planes but are diverted along the protein-inducedplanes, which absorb the force of impact,” explainsWeiner.

These findings might lead to the development of new crystal-polymer composites for building light-weight, tougher ceramics and improved electroopticmaterials.

Fine spine choices

Studies oof ssea uurchins aand mmollusks mmay lead tto ttougher mman-made mmaterials

You shall no longer give the people straw to makebrick as before (Exodus 5:6-7).

This is the first recorded account of a man-madecomposite, describing bricks used in ancient Egypt,which were made of mud mixed with straw. Thestraw increased the bricks’ thermal stability, pre-venting them from cracking. Modern studies showthat these bricks were three times stronger thanthose lacking straw. Thousands of years later, theEgyptian landscape is still dotted with monumentsmade of such bricks.

Composites are everywhere. Though often referringto the fiber-reinforced metals, polymers and ceramicmaterials originally developed for use in the 1950s,composite superstars include those found in nature– from human bone, to tree trunks, sea shells andspider dragline silk, which ounce for ounce isstronger than steel and tougher than kevlar.

Composite cornucopia

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A team of scientists has found that the brittlestar, amarine invertebrate long thought to be sightless, is infact covered with calcite crystals that function as opti-cal receptors for a compound eye. A better understand-ing of how to build such high-quality microlenses maylead to improved computer circuits.

Profs. Lia Addadi and Stephen Weiner of theWeizmann Institute’s Structural Biology Departmenthad long been interested in the ways in which animalsbuild their skeletal structures. When they met Dr.Gordon Hendler of the Natural History Museum ofLos Angeles County, Hendler brought to their attentionone particular species of brittlestar that appeared to beparticularly sensitive to changes in light, quickly escap-ing into dark crevices at the first sign of danger. Hesuspected that spherical crystal structures on the brit-tlestar’s outer skeleton serve as lenses, transmittinglight to its nervous system.

By analyzing the geometry of the crystal lenses Addadiand Weiner, together with their then graduate studentJoanna Aizenberg, were able to pinpoint the expectedfocal point on the nerve bundles below, but they lackedthe means of proving that these lenses indeed transmitlight to the nervous system within.

This is where things stood for almost ten years, untilthe team came up with the idea of examining the lensesusing lithography, a semiconductor technology.

Placing one of the crystals above a layer of photosensi-tive material, Aizenberg exposed the system to lightand found that it reached the photosensitive tissue inspots directly underneath the crystals. Her findings alsodemonstrated that the crystalline lenses act as “correc-tive glasses,” filtering and focusing light on photore-ceptors within the nerves. But unlike man’s ability tosee in virtually only one direction, this complex visualsystem enables the brittlestar to detect approachingdanger from many directions. The lenses expertly com-pensate for common optical distortion effects. Thisunique visual architecture has prompted hopes for new

materials that would mimic the brittlestar model.Knowing how to build such microlenses of high optical quality could lead to improved microlithographytools used in etching the integrated circuits found incomputers.

Prof. Lia Addadiholds the Dorothy and Patrick Gorman ProfessorialChair


Optical ssystem iin aancient mmarine ccreature may llead tto iimproved ccomputer ccircuits

“Sightless” marine creature found to be all eyes

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Peering into nature’s secrets

The cell – the elementary unit of life – is rich inengineering know-how. The ultimate self-assem-bler, it applies its molecular machinery to convertreadily available materials from food and waterinto a wonderland of materials – from over100,000 proteins, lipids and sugars, to the mate-rials they build: wood, bones, horns, scales andskin. It performs these feats in a tiny setting.Cells are generally only a few micrometers long,and their functional units, the organelles, areonly a few nanometers. Scientists around the

world are hard at work applying a range of toolsto chip away at the cell’s secrets by viewing andmanipulating nanoscale objects within andaround the cell.

Lessons from the cell, they believe, might provevital in understanding the basic mechanisms of life– the key to unprecedented medical advances. Thecell might also help in shaping our material world,with its varied nanostructures serving up solutionsto central challenges in material design.

Cells vary in length. Bacteria are about 1 micron long, while plant and animal cells vary from about 50 microns to meters inthe case of certain neurons.

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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 healingand the exchange of information between cells, knownas signaling. But how are these contacts formed andregulated? What cues within a living organism influence adhesion properties, instructing a cell tostick, move, proliferate or die?

Until recently, scientists studying the forces influencingcell adhesion faced a major difficulty: they lacked thetools to effectively identify and measure the minusculeforces applied between cells and their environment.Heading a multidisciplinary team, Prof. BenjaminGeiger of the Institute’s Molecular Cell BiologyDepartment developed a powerful new tool for study-ing cellular adhesion, which allows the measurement of forces in the Lilliputian range of nanonewtons (onenanonewton 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 patternedtemplate and applies a force, it distorts the grid. Bymeasuring these distortions, the scientists are able toinfer the magnitude and direction of the forces appliedby the cell to the contact area. This approach is proving

vital in revealing the interplay between adhesion andinternal cellular processes.

In related research, Geiger and Prof. AlexanderBershadsky of the Molecular Cell Biology Departmenthave shown that cells constantly “probe” their sur-rounding by touching and pulling at it. New researchquestions include the nature of the forces occurringbetween two cells as they anchor on the same substrate,a topic that plays a role in how cells aggregate to makea tissue and may thus have relevance to tissueengineering.

Other scientists participating in this research are Prof. LiaAddadi of the Institute’s Chemistry Faculty; Dr. NathalieBalaban, Polina Goichberg, Gila Tzur and Ilana Sabanay, allof the Molecular Cell Biology Department; Prof. Sam Safranand postdoctoral fellow Dr. Ulrich Schwarz of the Materials andInterfaces Department; Dr. Diana Mahalu of the SubmicronResearch Center; and Dr. Daniel Riveline, a postdoctoral fellowcurrently at Université Joseph Fourier in Grenoble, France.

Connect the dots

Tool tthat ccatches ccellular fforces iin tthe act mmay aadvance ttissue eengineering

Prof. Alexander Bershadskyholds the Joseph MossProfessorial Chair ofBiomedical Research

Prof. Lia Addadi holds the Dorothy and PatrickGorman Professorial Chair

Prof. Benjamin Geiger holds holds the Erwin Neter Professorial Chair of Cell and Tumor Biology

Prof. Sam Safran holds the Fern & Manfred SteinfeldProfessorial Chair

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In related research, Prof. Benjamin Geiger is workingto construct models that simulate the conditions experienced by cells as they move around the body. Intheir travels, cells encounter continuously changing“terrains” determined by the type of tissue they meet.They are able to sense the chemistry, geometry andmechanical properties of these environments and tomodify their behavior accordingly – for instance,applying extra adhesive force in settings lacking sufficient anchorage.

Collaborating with Prof. Lia Addadi of the Institute’sStructural Biology Department, Ph.D. student BaruchZimmerman and Prof. Yoachim Spatz of Germany’sHeidelberg University, Geiger is creating artificialmicro- and nanoscale models that simulate the body’svarying tissue matrices (collagen, fibers etc.) to obtain

a better understanding of the interactions between a cell and its environment – specifically, how a cell’sbehavior and motility are affected by the chemistry and mechanical properties of its environment. Insightsinto these questions may have implications in cancerresearch aimed at preventing the migration of cancer-ous cells to form metastases. The artificial models tested at the WIS may also advance tissue engineeringresearch, yielding knowledge of the type of scaffoldsneeded to create specific tissues.

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 dealswith the dispersion of a solid or liquid in another liq-uid. In his work at Exxon, Safran, today a professor inthe Institute’s Department of Materials and Interfaces,focused on unique “split-personality-like” moleculesused in oil extraction and recovery. Known asamphiphiles, these molecules have both polar (charged)and nonpolar regions. While one end is attracted topolar molecules such as water, the other end is generallya nonpolar hydrocarbon chain, attracted to oils or

lipids. This enables amphiphilic molecules to break upoil slicks into small droplets, which might then be further degraded by oil-eating microbes. The unique polar/nonpolar duality of amphiphilesmakes them key players in the body, where they self-assemble into an extremely rich assortment of soft mat-ter structures that perform regulatory and housekeepingchores. For instance, the membranes of all cells in thebody contain a nonpolar region facing the inside of thecell and a polar region on its surface, which is vital tothe cell’s interaction with nearby molecules. Anotherexample is that of micelles – a cluster of moleculescritical to efficient digestion, which break up otherwiseinsoluble fat molecules.

A better understanding of the body’s self-assemblingsystems may help in creating vesicles for use as potentdrug delivery systems.

How ddo ccells mmove aabout tthebody's cchanging tterrains?

Simulating life

Soft matter science

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Opening the gatesAs a red blood cell rushes through the arteries it isrepeatedly pounded, stretched and deformed as itpasses small capillaries, yet it rarely breaks apart.This feat is made possible by the fact that, like allsoft materials, cell membranes are relatively durablein their response to external forces.

Hoping to explore the relationship between cellfunction and the cytoskeleton (a structure just belowthe cell membrane that affects cell shape, divisionand adhesion) Prof. Safran and colleagues demon-strated that exposing live cells to a drug calledlatrunculin weakens the cytoskeleton, impairing itsincorporation of the actin protein.

This finding may lead to new tools for cancer diagnosis and drug development. When exposed toactin-impairing drugs, cancerous cells are stronglyaffected since their cytoskeleton is weak to beginwith, whereas healthy cells are generally better ableto maintain the integrity of their cytoskeleton.

This study was performed in collaboration with experimen-talist Prof. Elisha Moses of the Physics of Complex SystemsDepartment and Prof. Alexander Bershadsky of theMolecular Cell Biology Department as well as then graduate students, Roy Bar-Ziv and Tsvi Tlusty.

Soft materials and cancer diagnosis

What ddo ooil sspills, ddigestion aand cancer ddiagnosis hhave iin ccommon?

Prof. Sam Safran holds the Fern & Manfred SteinfeldProfessorial Chair

Prof. Elisha Moses Prof. Alexander Bershadskyholds the Joseph MossProfessorial Chair ofBiomedical Research

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Opening the gates

In biblical times, the gate was the most vulnerablepoint of a walled city. Judges were placed there tointerview travelers, verifying that their presence waswelcome. The same is true of the gates to the cell’sinner 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 enteringthe 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 anothermolecule – messenger RNA – which exits the nucleusthrough the same gates.

Understanding the mechanism by which molecules pass the nucleus’ gates is crucial to controlling suchtraffic. These methods may be applicable in barring theentry of viruses into the cell’s nucleus, or in gene thera-py, in which a beneficial gene is introduced into thepatient’s DNA to replace a damaged counterpart gene.

Dr. Michael Elbaum of the Weizmann Institute’sMaterial and Interfaces Department is studying the passage of DNA molecules through these gates usingoptical and electron microscopy. His team applies atool based on tiny tweezers composed of laser beamsfocused in a microscope.

In collaborative research with Prof. AlexanderBershadsky of the Molecular Cell Biology department,Elbaum and his team applied similar optical tweezers to probe cell adhesion and its relation to cell movementin the body – phenomena playing a key role in embry-onic development, wound healing and other fundamen-tal life processes.

The team designed small beads coated with proteinsinvolved in adhesion. They then used the optical tweezers to hold the beads over the cell surface andmap their resulting interaction with the cell. In the

study, published in Biophysical Journal, they showedstriking differences in the way different regions of thecell surface respond to the stimuli generated by the adhesion proteins, making it possible to pinpoint specific regions where adhesion takes place.

Dr. Michael Elbaum Prof. Alexander Bershadskyholds the Joseph MossProfessorial Chair ofBiomedical Research

Optical ““tweezers” rreveal tthe rrules of ccellular aadhesion aand ttraffic

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In more materials-oriented research, Elbaum and histeam are currently studying a central ingredient ofthe 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 shapedas hollow, rigid, chimney-like structures. The celluses microtubules for communication and delivery,

sending “packages” running along them, driven byspecialized motor proteins.

Studies of this system are shedding light on molec-ular traffic in the cell. Since microtubules are elasticpolymers, such studies may also yield a better understanding of the dynamics of both natural andsynthetic polymers, revealing properties important to a range of applications, from food packaging toindustrial glues.

Skeletal surveying tool

Every time we breathe, the oxygen drawn into our lungsbinds to iron atoms present in hemoglobin molecules inthe blood. The hemoglobin transports the oxygen tocells throughout the body, where it is released and usedto produce energy. Iron’s ability to bind, release andactivate oxygen stems from its capacity to“give” and“receive” electrons. In this respect, it is similar toother metals such as copper, cobalt and nickel. Thesemetals underlie the actions of numerous enzymes _

“molecular machines” essential for nearly all cellularprocesses.

Prof. Daniella Goldfarb, of Institute’s ChemicalPhysics Department, is studying metalloenzymes(enzymes containing iron and other metals) with theaim of mapping the precise structure of their metal-containing active sites. Insights in this field will helpadvance the construction of molecular machines – 10 to 50 nanometers large – that, equipped with thesemetal-containing active sites, would be capable of per-forming diverse industrial functions, some dramaticallyimproved from existing technologies.

A good example is that of ammonia production – areaction that calls for extreme temperatures and pres-sure when performed industrially, yet is synthesized inbacteria in a series of elegant biochemical reactions, at

ambient temperatures and without the production ofharmful byproducts.

Mapping the metal-containing sites may also lead tomethods for repairing damaged enzymes, offering aninvaluable medical tool since damaged or faultyenzymes lie at the root of many diseases.

Metal ‘a day to keep diseases away

Prof. Daniella Goldfarb

Metal-mapping sstudy ttargets repair ttool ffor ddamaged eenzymes

Nano 2nd 3/11/2004 2:45 pm Page 67

Proteins, the fundamental components of all livingcells, start out as randomly shaped chains and twistinto a well-defined structure that determines their function. A botched job of protein folding has beenlinked to a growing list of diseases, includingAlzheimer'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 moleculesunderwent and could not pick up individual differ-ences. This shortcoming highlighted the need for a new technology that would make possible the study of individual proteins as they fold – a huge challengesince 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 PhysicsDepartment has made the first glimpses ever of singleproteins in the process of folding. The technology’ssuccess lies in striking the right balance. Since proteinsare continuously active, one must limit their motion toget a clear understanding of their folding process.However, a fully immobilized protein defeats the pur-pose. It won’t fold. Earlier attempts to gain a steadylook at proteins sought to pin them down to a surface;but this could be achieved only by binding the proteinto a surface, thus changing its properties.

To skirt this obstacle, Haran’s team designed novelvesicles that envelop the proteins in question. Eachvesicle is 100 nanometers wide and designed to envel-op a single protein molecule, generally only 3-4nanometers long. Unaware of their scientist-made borders, the proteins can move about freely, yet not soactively as to impair the scientists’ ability to observetheir behavior.

The results verify what theoretical scientists have sus-pected for nearly a decade – that proteins may vary intheir folding process. Even identical proteins ending up

with the same shape may take different routes to reachit. The new WIS technology might help clarify the reasons for protein misfolding and ensuing disease.

68

Nano-visualization ttechnology mmay open wwindow oon pprotein mmisfolding and eensuing ddisease

Dr. Gilad Haran holds the Benjamin H. Swig andJack D. Weiler CareerDevelopment Chair

First sightings of individual proteins as they fold

Nano 2nd 3/11/2004 2:45 pm Page 68

69

Dr. Ernesto Joselevich holds the Dr. Victor L. Ehrlich Career Development Chair

Nanosized pprobe eexplores llive, moving DDNA

DNA? Proteins? Fish ‘em out with a nanoprobe

Coupling the delicate touch of a nanotube probe withatomic force microscopy (AFM), Dr. Ernesto Joselevichis able to produce today’s highest-resolution images oflive, moving DNA.

AFM works like a record player “reading” surfaceswith a needle-fine tip; it rises and descends as it meets“bumps” or “valleys” in the target surface. Thesemotions are translated via a computer to create anatomic-scale image. But while AFM provides detailedtopographical information, it offers only limited information about an object’s surface chemistry. “It’slike being able to determine where a cake is withoutknowing whether it’s a chocolate swirl or blueberrywith cream,” says Joselevich, of the Institute’sMaterials and Interfaces Department.

Seeking to enhance the tool’s sensitivity, Joselevich, at the time completing a post-doc at Harvard underProf. 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 probewith nanotubes fitted with different chemical tips, suchas molecules that might interact with those on the target surface. By detecting binding forces betweenthese chemical tips and the target surface, he reasoned,one might gain new information about the surfacechemistry.

Another motivation was the nanotube’s tiny diameter.The team hypothesized that they could significantlyincrease 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 inradius. “A blunt tip makes it difficult to detect fineobjects. It’s like trying to feel or pick up a grain of ricewith a boxing glove,” explains Joselevich.

The study, published in Nature, showed that he was onthe mark. The new approach successfully detects thepresence of specific molecules on the target surface.Likewise, having added a temporal resolution systemthat photographed the interaction every 30 seconds,

Joselevich is able to view live, moving DNA as itundergoes various biochemical processes. This real-time view offers an important advantage over electronmicroscopy, which can be applied only to dead sam-ples, since the high flow of electrons intrinsic to thattechnology destroys the sample.

Potential future applications of chemical forcemicroscopy range from basic research aimed at a betterunderstanding of gene expression, to the ability todetect a person’s susceptibility to disease, to industrialapplications, including the detection of chemical impurities on semiconductor chips.

Nano 2nd 3/11/2004 2:45 pm Page 69

Nanoscience research at the Institute is under the auspices of the Joseph H. and Belle R. Braun Center forSubmicron Research and the newly established Helen and Martin Kimmel Center for Nanoscale Science.

The Joseph H. and Belle R. Braun Center for Submicron Research was founded in 1991 to explore the behav-ior of miniature systems, including electronic devices. This research concerns the mesoscopic realm of physics,the “twilight zone” that lies between the macroscopic world (visible to the eye or under an optical microscope)and the microscopic world of individual atoms. Something extraordinary happens around this dimensional border– the Newtonian laws of physics give way to those of quantum mechanics, in which subatomic particles of mattermay appear and behave as either particles or waves. Research into this realm may facilitate the development ofultrapowerful electronics governed by quantum phenomena, such as instruments that could measure the electricalactivity of the heart without so much as touching the patient, supercomputers the size of a pinhead and evenminuscule robots.

The Helen and Martin Kimmel Center for Nanoscale Science emphasizes the integration of nanofabricationwith biotechnology, bringing together researchers from these traditionally unrelated fields in novel projects rang-ing from the development of artificial circuits that integrate DNA onto silicon chips for the study of protein pro-duction, to sensors that use electronic chips laced with biological molecules for the detection of chemical com-pounds.

Having the facilities for sample preparation and analysis in close proximity to each other, and under the auspicesof the Kimmel Center, promotes the cross fertilization of ideas as well as the efficient use of shared resources.Many of the projects and processes are iterative ones, in which a sample is prepared (perhaps by lithography orself-assembly in a clean room), checked and/or modified at a device analysis laboratory, and returned to the cleanroom for further work.

The Kimmel Center includes four facilities, which operate both independently and in close collaboration:

The Nanosciences Facility, which includes two separate but complementary facilities: the NanofabricationLaboratory, consisting of a state-of-the-art clean room with photolithography and electron-beam lithography systems, and the DNA Manipulation Laboratory, used for preparing and manipulating DNA molecules. Thesespecimens are then tethered to silicon chips for various projects, including electrically activated genetic transducers.

The Nanomaterials Synthesis Laboratory, which allows for the high-precision synthesis of nanomaterialsaccording to targeted size and shape.

The Device Analysis Laboratory, which applies physical chemistry and optics to analyze the chemical andmechanical properties of nanostructures. Tools used in the lab include material characterization applications, suchas the Raman and scanning probe microscopes as well as various X-ray apparatus.

The Computational Nanosciences Laboratory, which includes a “supercomputer” consisting of 60 microproces-sors working in parallel, is used to perform very large computational operations to help predict the properties ofdifferent nanomaterials.

Nanoscience Facilities at the Institute

Nano 2nd 3/11/2004 2:45 pm Page 70

Prof. Lia Addadi (p. 60, 61, 63, 64)

Research supported by:

The Ilse Katz Institute for Material Sciences and Magnetic

Resonance Research; Minerva Stiftung Gesellschaft fuer

die Forschung m.b.H.; the Women’s Health Research

Center and the Ziegler Family Trust, Encino, CA

Prof. Lia Addadi is the incumbent of the Dorothy and

Patrick Gorman Professorial Chair

Dr. Uri Alon (p. 13)


The Charpak-Vered Visiting Fellowship, Canada; the Clore

Center for Biological Physics; the Leon & Gina Fromer

Philanthropic Fund; Minerva Stiftung Gesellschaft fuer die

Forschung m.b.H.; the James and Ilene Nathan Charitable

Directed Fund; the Mrs. Harry M. Ringel Memorial

Foundation; the Estate of Ernst and Anni Deutsch,

Liechtenstein; Mr. and Mrs. Mordechai Segal, Israel; Mr.

Andrew Shechtel, Princeton, NJ and the Yad Abraham

Research Center for Cancer Diagnostics and Therapy

Dr. Alon is the incumbent of the Carl & Frances Korn

Career Development Chair in the Life Sciences

Prof. Ilya Averbukh (p. 13)


The Wolfson Advanced Research Center

Prof. Averbukh is the incumbent of the Patricia Elman

Bildner Professorial Chair of Solid State Chemistry

Prof. Israel Bar-Joseph (p. 33, 47)


The Joseph H. and Belle R. Braun Center for Submicron

Research

Prof. Bar-Joseph is the incumbent of the Jane and Otto

Morningstar Professorial Chair of Physics

Dr. Roy Bar-Ziv (p. 39, 65)


Sir Charles Clore Prize – The Clore Foundation;

Clore Center for Biological Physics; the Philip M.

Klutznick Fund for Research; Levy-Markus Foundation;

the Lord Sieff of Brimpton Memorial Fund and Sir Harry

Djanogly, CBE

Dr. Bar-Ziv is the incumbent of the Beracha Foundation

Career Development Chair

Our ThanksThe Weizmann Institute of Science gratefullyacknowledges the support of its friends whohave contributed to material science researchover the years.

Nano 2nd 3/11/2004 2:45 pm Page 72

Prof. Alexander Bershadsky (p. 63, 65, 66)


The Yad Abraham Research Center for Cancer

Diagnostics and Therapy

Prof. Bershadsky is the incumbent of the Joseph Moss

Professorial Chair of Biomedical Research

Prof. David Cahen (p. 12, 33, 41, 49)


The Philip M. Klutznick Fund for Research; Delores and

Eugene M. Zemsky Weizmann-Johns Hopkins Research

Program; Minerva Stiftung Gesellschaft fuer die

Forschung m.b.H. and the Wolfson Advanced Research

Center

Prof. Cahen is the incumbent of the Rowland Schaefer

Professorial Chair in Energy Research

Dr. Hagai Cohen (p. 10)

Dr. Cohen is a recipient of the Dr. Maxine Singer

Outstanding Research Associate Prize

Dr. Sidney Cohen (p. 24, 28, 33, 49)


Dr. Michael Elbaum (p. 66)


The Clore Center for Biological Physics and Teva

Pharmaceuticals

Prof. Asher Friesem (p. 55)

Prof. Friesem is the incumbent of the Peter and Carola

Kleeman Professorial Chair of Optical Sciences

Dr. Konstantin Gartsman (p. 12, 49)

Dr. Gartsman is a recipient of the Dr. Maxine Singer

Outstanding Research Associate Prize

Prof. Yuval Gefen (p. 44)

Prof. Gefen is the incumbent of the Isabelle and SamuelFriedman Chair of Theoretical Physics

Prof. Benjamin Geiger (p. 13, 63, 64)


The Estate of Evelyn Blum, Switzerland; the Clore Center

for Biological Physics; the Estate of Ernst and Anni

Deutsch, Liechtenstein; the Ilse Katz Institute for Material

Sciences and Magnetic Resonance Research; the Levine

Institute of Applied Science; the Women's Health

Research Center

Prof Geiger is the incumbent of the Erwin Neter

Professorial Chair of Cell and Tumor Biology. He heads

the Clore Center for Biological Physics

Prof. Daniella Goldfarb (p. 15, 67)


The Fritz Haber Center for Physical Chemistry; the

Sonnie and William Dockser Research Fund; the Ilse Katz

Institute for Material Sciences and Magnetic Resonance

Research and the Gerhard M.J. Schmidt Minerva Center

for Supramolecular Architecture

Dr. Gad Haase (p. 13)

Dr. Gilad Haran (p. 68)


The Clore Center for Biological Physics; the Fritz Haber

Center for Physical Chemistry and the Avron-Wilstaetter

Minerva Center for Research in Photosynthesis

Dr. Haran is the incumbent of the Benjamin H. Swig and

Jack D. Weiler Career Development Chair

Prof. Moty Heiblum (p. 46, 50)


The Joseph H.and Belle R. Braun Center for Submicron

Research; Mr. Josph Gurwin, New York, NY; Mr. and

Mrs. Harold Simpson, Delray Beach, FL.; the Wolfson

Advanced Research Center and Dan Mayer, France

Prof. Heiblum is the incumbent of the Alex and Ida

Sussman Professorial Chair in Submicron Electronics

Prof. Gary Hodes (p. 36)


The Levine Institute of Applied Science

Nano 2nd 3/11/2004 2:45 pm Page 73

Prof. Yoseph Imry (p. 50)


The late Mr. Simon Bond, New York, NY; the Albert

Einstein Center for Theoretical Physics and the Maurice

and Gabriela Goldschleger Center for Nanophysics

Prof. Imry is the incumbent of the Max Planck

Professorial Chair of Quantum Physics

Dr. Ernesto Joselevich (p. 23, 69)


Sylvia and Henry Legrain, Spain; Sir Harry A.S.

Djanogly, CBE, UK.; the Philip M. Klutznick Fund for

Research and the Ilse Katz Institute for Material Sciences

and Magnetic Resonance Research

Dr. Joselevich is the incumbent of the Dr. Victor L.

Ehrlich Career Development Chairs

Prof. Jacob Klein (p. 57)

Prof. Klein is the incumbent of the Hermann Mark

Professorial Chair of Polymer Physics

Dr. Leeor Kronik (p. 45)


The Estelle Funk Foundation and Sir Harry Djanogly, CBE

Dr. Kronik is the incumbent of the Delta Career

Development Chair

Prof. Meir Lahav (p. 9)


Mr. Marvin Reinstein, Amityville, NY; the Ilse Katz

Institute for Material Sciences and Magnetic Resonance

Research; the Fritz Haber Center for Physical Chemistry

and the Gerhard M.J. Schmidt Minerva Center for

Supramolecular Architecture

Prof. Lahav is the incumbent of the Margaret ThatcherChair of Chemistry

Prof. Leslie Leiserowitz (p. 9).


Helen & Milton A. Kimmelman Center for Biomolecular

Structure & Assembly and the Joseph and Ceil Mazer

Center for Structural Biology

Dr. Gregory Leitus (p. 34, 48)

Dr. Igor Lubomirsky (p. 31)

Dr. Lubomirsky is the incumbent of the Helen & Milton

Kimmelman Career Development Chair

Dr. Rivka Maoz (p. 27, 28)

Prof. Elisha Moses (p. 65)


Clore Center for Biological Physics

Rosa and Emilio Segre Research Award

Prof. Ron Naaman (p. 12, 34, 40)


The Fritz Haber Center for Physical Chemistry; the Ilse

Katz Institute for Material Sciences and Magnetic

Resonance Research; the Philip M. Klutznick Fund for

Research; Dr. Pamela Scholl, Northbrook, IL and the

Wolfson Advanced Research Center

Prof. Naaman is the incumbent of the Aryeh and Mintze

Katzman Professorial Chair

Prof. Yehiam Prior (p. 13, 32)


The Gerhard M.J. Schmidt Minerva Center for


Prof. Prior is the incumbent of the Sherman Professorial

Chair of Physical Chemistry

Dr. Michael Rappaport (p. 47)


Prof. Shimon Reich (p. 34, 48)

Prof. Israel Rubinstein (p. 10, 15, 25, 36, 42)


The Clore Center for Biological Physics; the Edward D.

and Anna Mitchell Family Foundation; the Philip M.

Klutznick Fund for Research; the Fritz Haber Center for

Physical Chemistry; Minerva Stiftung Gesellschaft fuer

die Forschung m.b.H. and the Angel Faivovich Foundation

for Ecological Studies

Prof. Samuel Safran (p. 21, 63, 64)


The Dolfi and Lola Ebner Center for Biomedical Research

Prof. Safran is the incumbent of the Fern & Manfred

Steinfeld Professorial Chair

Nano 2nd 3/11/2004 2:45 pm Page 74

Prof. Jacob Sagiv (p. 27, 28)


The Gerhard M.J. Schmidt Minerva Center for


Prof. Menahem Segal (p. 12)

Prof. Abraham Shanzer (p. 10, 12, 13, 41, 42)


The Helen and Martin Kimmel Center for Molecular

Design; the Edward D. and Anna Mitchell Research Fund;

the Gerhard M.J. Schmidt Minerva Center for

Supramolecular Architecture and the Angel Faivovich

Foundation for Ecological Studies

Prof. Shanzer is the incumbent of the Siegfried and Irma

Ullmann Professorial Chair

Prof. Ehud Shapiro (p. 56)


The Samuel R. Dweck Foundation; the Dolfi and Lola

Ebner Center for Biomedical Research; the Benjamin and

Seema Pulier Charitable Foundation; the Robert Rees

Fund for Applied Research and the M.D. Moross Institute

for Cancer Research

Prof. Reshef Tenne (p. 20, 21)


The Alfried Krupp von Bohlen und Halbach Foundation;

Applied Materials, Israel; Minerva Stiftung Gesellschaft

die Forschung m.b.H. and the Helen and Martin Kimmel

Center for Nanoscale Science

Dr. Vladimir Umansky (p. 46, 47)


Dr. Milko van der Boom (p. 30)


The Henri Gutwirth Fund for Research ITEK, Israel; the

Helen and Martin Kimmel Center for Molecular Design

and Sir Harry A.S. Djanogly, CBE, UK

Dr. van der Boom is the incumbent of the Dewey D. Stone

& Harry Levine Career Development

Dr. Alexander Vaskevich (p. 10, 15, 25)

Prof. Zeev Vager (p. 34)

Prof. Shimon Vega (p. 15)


The Fritz Haber Center for Physical Chemistry; the

Gerhard M.J. Schmidt Minerva Center for Supramolecular

Architecture Sonnie and the William Dockser Research

Fund

Prof. Vega is the incumbent of the Joseph and Marian

Robbins Professorial Chair

Prof. Daniel Wagner (p. 16, 24, 59)

Prof. Wagner is the incumbent of the Livio Norzi

Professorial Chair

Prof. Stephen Weiner (p. 55, 59, 60, 61)


The Helen and Martin Kimmel Center for Archaeological

Science; the Philip M. Klutznick Fund; the Alfried Krupp

von Bohlen und Halbach Foundation; George

Schwartzman, Sarasota, FL and the Women's Health

Research Center

Prof. Weiner is the incumbent of the Dr. Walter and Dr.

Trude Borchardt Professorial Chair in Structural Biology

Prof. Amir Yacoby (p. 44, 50, 51)


The Rosa and Emilio Segre Fund Joseph H. and the Belle

R. Braun Center for Submicron Research

Nano 2nd 3/11/2004 2:45 pm Page 75

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