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Science Feature Articles</p>

Found in the Desert

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(l-r) Gilad Landan, Dr. Amos Tanay and Rami Jaschek. New targets for treatment

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer begins in the genes: When certain genes become over or under active, the ensuing deregulation of cell growth, reproduction and death leads to cancer. But researchers attempting to identify specific genetic markers that signify a predisposition to cancer or hoping to find a gene-based cure have been largely disappointed.
 
One reason for this, says Dr. Amos Tanay of the Weizmann Institute’s Computer Science and Applied Mathematics Department, is that scientists may have been conducting too narrow a search. In a recent study published in the online journal PLoS Genetics, Tanay and a team of scientists – including mathematicians and geneticists from three different research groups – turned their sights on a large “gene desert,” using powerful new methods to comb a vast stretch of genomic information for variations that may increase cancer risk, as well as providing possible new targets for treatment.
 
The long expanses of chromosomal DNA known as gene deserts are basically devoid of the genes that code for protein production, but they’re hardly barren. Genes make up only a fraction of the DNA in our cells; scientists have come to realize in recent years that much of the so-called “non-coding” DNA influences gene activity at various stages, forming a complex system of checks and balances that regulates the process.
 
One such gene desert, a long segment of chromosome 8, had been implicated in cancer. The region, called 8q24, is half a million bases (“letters” of the gene code) long, and at first there was little way to make sense of the finding. “But the newest revolution in DNA sequencing technology enabled us to examine the entire region in a single experiment and to zoom in on the really important cancer-related genetic variations,” says Tanay.
 
Together with his research students Gilad Landan and Rami Jaschek, as well as Gerhard Coetzee and Li Jia of the University of Southern California, Matthew Freedman of Harvard University and others, Tanay used the new rapid sequencing and microarray methods together with the advanced analysis techniques they developed, to map an area of the chromosome covering millions of bases. Their search was for activity in single-nucleotide polymorphisms, or SNPs (pronounced “snips”) – places where the DNA codes tend to vary among people by one or two letters.
 
After they had succeeded in assembling a color-coded map of the region, the scientific team was able to identify “hot spots” – regions of unusual activity. Next they zoomed in on these hot spots, isolating suspect sequences and inserting them into cells in the lab to see how these would affect cell function.
 
Several of the DNA sequences the researchers identified were indeed seen to be “enhancers” – bits of code for ratcheting up gene activity. Enhancers created by modifying normal DNA sequences to make them similar to those in cancer patients were much more active than the normal variants. This allowed the researchers to narrow down the list of genetic variations suspected of promoting cancer from many thousands to just a few.
 
But how can a change in one nucleotide amid half a million letters cause cancer? And which gene (or genes) was being enhanced by the newly discovered variants? The answers might be found just past the outskirts of the 8q24 gene desert, where a gene called Myc is located. Heightened Myc activity is associated with many types of cancer, so a connection is likely.
 
Myc may be the SNP’s nearest gene neighbor, but they’re still “kilometers” apart as far as DNA sequences go. Nonetheless, Tanay and Landan believe that they communicate directly, with the whole DNA strand folding over to bring the two into physical contact. It’s a phenomenon recently witnessed in another 8q24 DNA sequence, and they think such folding might be fairly common in the cancer genome, enabling distant bits of code – even those residing way out in the middle of gene deserts – to directly regulate the genes. “We’re used to thinking of the genetic code as an orderly sequence, but it appears to be more like spaghetti – or like the Internet, with hyperlinks all over the place,” says Tanay. “We’re starting to untangle these processes, and our findings seem to point to new directions for more effective prevention, diagnosis and treatment.”
 
Dr. Amos Tanay’s research is supported by Pascal and Ilana Mantoux, Israel.

 
The Math of Life

Born on Moshav Moledet in Israel, Dr. Amos Tanay earned his B.Sc. and M.Sc. in mathematics from Tel Aviv University. While in graduate school, he headed a research team that developed algorithms for an optimization company, Schema Group, then cofounded an optical networks technology start-up, Optivera Technologies, and headed its R&D effort for two years. However, Tanay soon decided his true interest was biological research, and he returned to Tel Aviv University, obtaining his Ph.D. in computational biology in 2005. After conducting postgraduate research in Rockefeller University’s Center for Studies in Physics and Biology, he joined the Weizmann Institute as a senior scientist in 2007. The thrill of science, for Tanay, is that “there’s always something new. You can ask big questions and find answers, but those answers will always lead to a new set of questions.”
 
Tanay is married and the father of three children. He is a keen jazz musician in his scarce spare time.
(l-r) Gilad Landan, Dr. Amos Tanay and Rami Jaschek. New targets for treatment
Math & Computer Science
English

The Bat Has Landed

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Dr. Nachum Ulanovsky and Dr. Yossi Yovel. New angle on sonar

 

 

 

 

 

 

 

 

 

 

 

 

 

Need to track a moving object in the dark? The best method might not be shining your flashlight directly at it. New research on bats shows you could do better by angling the beam a bit to the left or right of your object. The illumination will be dimmer toward the edges of the expanding cone of light, but it will be easier to make out the object’s direction as it moves in relation to the brighter center. In research that recently appeared in Science, Dr. Nachum Ulanovsky and postdoctoral fellow Dr. Yossi Yovel of the Weizmann Institute’s Neurobiology Department showed that bats, which “see” with beams of sound waves, locate an object by aiming their sonar beam to either side of an object, catching it on the cone’s fainter slope, rather than at the central peak.

Animal sonar, or echolocation, is a type of active sensing: The animal must send out a signal in order to get back information on its surroundings. It works remarkably like the sonar that submarines use to find enemy ships: The bats (or ships) emit a sound and listen for the echo, accurately judging the type and location of objects around them by the changes in the sound waves as they’re reflected back. This gives biologists studying echolocation a unique research tool: The mathematical formulas that have been worked out by sonar engineers can generally be applied also to animal echolocation. In keeping with this tradition of applying mathematical thinking to animal sonar, the Weizmann scientists theorized that there should be a trade-off in efficiency between the detection of an object and determining its exact location. For a bat, this could mean that a bug hidden among leaves is best found by focusing with the peak intensity of the sound beam, whereas a large moth flitting out in the open – easy to detect but hard to locate – could best be tracked by aiming the beam off-center to make use of its maximum slope; this turns out to be the most sensitive strategy for detecting changes in the moth’s location.

But are the bats actually behaving according to this prediction – that is, are they able to fit their echolocation strategy to the situation? To answer this question, a research team headed by Ulanovsky trained bats to locate and land on a large black sphere placed randomly in a completely dark room. The bats had to rely solely on echolocation to navigate. A string of special microphones arrayed around the room’s walls traced the sound waves the bats emitted, while two infrared video cameras tracked their flight patterns.

The large Egyptian fruit bats in Ulanovsky’s lab have a unique echolocation system. Unlike many smaller bat species that emit regularly-spaced ultrasonic squeaks, these bats produce their signals in clicks, two at a time. The researchers thought that these double clicks might hold some clues to the bats’ localization strategies. Sure enough, the team, which included Prof. Cynthia Moss and research student Ben Falk from the University of Maryland, found a pattern: The first set of double clicks was aimed left and then right, the next set right and then left. As the bats closed in for a landing, they continued to throw their sound beams to alternate sides of the sphere, just where the mathematical formula predicted they would be most effective. The sphere was designed to be easily detectable, meaning the bat’s optimal strategy was one of localization. To create a situation in which detection was needed as well as localization, the scientists installed a large panel behind the sphere that echoed the sound waves back to the bats’ ears. Now, instead of identifying the sphere’s echo in a quiet room, they had to pick it up out of a battery of noise. This time, as the bats approached their target, they began to narrow their sweep and aim the beams more or less directly toward the sphere.

Large Egyptian fruit bat
 

Ulanovsky: “We were surprised to find that no one had asked these questions before us. Not only did we show that the optimal method for tracking an object is to catch it off-center, on the slope of a beam, we also demonstrated that bats are capable of balancing between detection and localization, and adopting the best strategy according to the particular need.” Active sensing takes place in many situations: Sonar and radar bounce off moving vessels or airplanes, dolphins and whales echolocate in the oceans, dogs track objects by sniffing, and our eyes move in all directions as they interact with our surroundings. Even bacteria use a type of chemical sensing to move toward or away from nearby substances. Ulanovsky and Yovel believe that what works for bats may well work for other organisms: In the future, scientists might find that “sensing on the slope” could be a useful strategy for any or all of these.


Dr. Nachum Ulanovsky’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the J&R Foundation; and Rita and Steven Harowitz, Tiburon, CA.

 
 
Dr. Nachum Ulanovsky and Dr. Yossi Yovel. New angle on sonar
Life Sciences
English

Crowd Control

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Dan Bracha, Prof. Roy Bar-Ziv, Dr. Shirley Daube and Dr. Amnon Buxboim

 

 

 

 

 

 

 

 

 

 

 

 

An observer in a busy train station will soon notice that the crowd is denser near ticket counters, kiosks and platforms. No walls separate the different activities, but each nevertheless occupies a distinct compartment within the space. Weizmann Institute scientists have now applied a similar principle to genes, packing them together in small areas on a chip. In the process, they are revealing the ways in which such “crowd management” might help to control the activities of genes in cells. Their method could not only provide new tools to realistically manipulate genes in lab experiments; it might prove to be an essential step in the quest to create artificial cells.
 
Gene activity in biological organisms takes place in the cramped quarters of the cell or, if the organism is not a bacterium, in the tight space of the cell nucleus. And recent evidence has suggested that within the jam-packed nucleus some of those activities are segregated into distinct areas. Yet lab experiments with genes typically use strands of DNA and various other molecules floating loosely in solution. Prof. Roy Bar-Ziv of the Institute’s Materials and Interfaces Department in the Faculty of Chemistry wanted to create a system that would combine the convenience of the test tube with the crowded conditions in a cell. Together with then doctoral student Amnon Buxboim, he developed a method for attaching fairly long strands of DNA perpendicularly onto a surface to create a thick, brush-like carpet. With the aid of a photo-lithography technique borrowed from microelectronics, they managed to control the density so precisely that they were able to create highly detailed, nanosized “photographs” printed in DNA.
 
Once they had perfected the technique, Bar-Ziv, Buxboim, research student Dan Bracha and Dr. Shirley Daube, who directs the Institute’s Chemical and Biophysical NanoSciences labs of the Chemical Research Support Department, began to investigate what dense DNA “brushes” might reveal about gene activity at close quarters. Starting out with the simplest scenario, they created DNA brushes containing one type of gene and then observed the first stage of gene activity – the assembly of RNA strands from the genetic code – comparing this with the activities of DNA strands floating in solution.
 
The gene brushes created by the team did, indeed, act as tiny compartments, exhibiting properties that set them apart from their surroundings despite the lack of any physical barrier. The scientists tried out the gene brushes in different conditions – by changing the salt levels in the environment, for instance, or adding substances that affect DNA activity – and found that the crowded genes mimicked the actions of genes in cells much more closely than the free-floating control genes.
 
The team also experimented with variations on the brushes themselves: They increased or decreased the spacing between the genes; they added more or less “junk DNA” (non-coding DNA) between the genes and, finally, they flipped the genes over, so that one time the bit of DNA that gives the “begin copying here” signal was facing the free end and another time sat facing the attached end.
 
All of these changes affected the rate at which the genes worked – even the junk DNA. Greater crowding slowed things down, as did flipping the genes so the “start” codes were lower down. Dense placement appeared both to limit the access of the RNA copying machinery to the genes and to keep that machinery and the resulting RNA within the compartment area for longer. In addition, the researchers found that this arrangement enabled them to control the direction (and thus the protein output) in which the genetic information was copied – something that’s not possible in solution but happens as a matter of course in cells.
 
Although living cells don’t have their genes neatly lined up in rows, the scientists believe the dense brushes can provide some interesting insights into how the physical arrangement of DNA affects its workings. They think that junk DNA, for instance, which makes up around 90% of the DNA in our cells, might function as a sort of packing material that helps to maintain a certain level of density. The findings hint that some sort of open-plan compartmentalization may be a common, space-efficient strategy for keeping order in the busy cell. Such compartments, says Bar-Ziv, could even have preceded enclosed cells: “Rather than originating inside a membrane, the first cells might have started from a membrane-free compartment of complex molecules that clumped together, and this may have remained a basic organizing principle.”
 
Bar-Ziv: “The multidisciplinary skills of the team – Amnon and I come from a physics background, Shirley is a biochemist and Dan’s background is bioengineering – are what made this research possible.” He and his research team plan to keep refining their gene brushes, experimenting with more complex situations, including arrangements of multiple genes and gene recombination. “Eventually, we would like to build an artificial chromosome, and even an artificial cell. Unlike today’s gene chips, which are passive identification tools, the genes in our brushes are active, and we want to learn how to direct their actions.”

 
Prof. Roy Bar-Ziv’s research is supported by the Phyllis and Joseph Gurwin Fund for Scientific Advancement; the Helen and Martin Kimmel Center for Nanoscale Science; and the Carolito Stiftung.
 
(l-r) Dan Bracha, Prof. Roy Bar-Ziv, Dr. Shirley Daube and Dr. Amnon Buxboim. Close quarters Wall-free compartments might keep gene activities in order
Chemistry
English

Capturing Cancer

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Prof. Amos Breskin and team. Imaging prostate cancer
 
 
Military intelligence enables us to prepare for untoward events, improving our chances of curbing them. Likewise, “medical intelligence” – the early diagnosis of diseases, including cancer – can buy information and time, crucial factors that can significantly increase chances of recovery. For this reason, scientists all over the world are striving to develop advanced methods for the early diagnosis of cancer.
 
Prostate cancer is the second most common lethal cancer in men over 60, claiming a quarter of a million lives worldwide each year. There is a need for new methods that can provide reliable and sensitive early detection. Currently, recommended screening for prostate cancer is based on a combination of digital rectal examination, ultrasound and testing the amount of a prostate protein, PSA, in the blood. But these methods are neither sensitive nor reliable enough: Often the tests fail to sound the alarm bells, leaving the cancer to grow undetected, while in a considerable number of cases the tests set off false alarms, flagging benign and non-malignant conditions as potentially cancerous. In addition, these screening tests do not provide information about the exact size or location of the tumor and, worse, they are unable to determine the aggressiveness or clinical stage of the tumor. As a result, many older men are referred for biopsies, which, in as many as three out of four cases, prove negative (though even biopsies can produce false negatives). Because a biopsy is a painful and costly procedure, many scientists worldwide are searching for a non-invasive alternative.
 
Prof. Amos Breskin and Dr. Rachel Chechik, together with Dr. Sana Shilstein and research student Marco Cortesi of the Weizmann Institute’s Particle Physics and Astrophysics Department, in collaboration with Dr. David Vartsky of Soreq NRC, have recently developed a new concept for prostate cancer diagnosis. The method, which begins by detecting prostate zinc levels with X rays, is presently being tested in clinical trials in collaboration with Prof. Jacob Ramon and Drs. Eduard Fridman, Gil Raviv, Alexander Volkov and Nir Kleinman of Sheba Medical Center, Tel Hashomer; as well as Drs. Evyatar Moriel, Monica Huszar, Gabriel Kogan and Valery Gladysh of Kaplan Medical Center, Rehovot.
 
The method derives from three-decade-old observations that the concentration of zinc – an element found naturally and abundantly in healthy prostatic tissue – is low in the prostates of men suffering from advanced prostate cancer. The last decade has brought further insight into the role of zinc in the prostate; it’s involved, among other things, in the secretion of citrate-rich prostatic fluid.
 
The research team wanted to know whether a prostate zinc deficiency could be identified in earlier stages of cancer. They performed a clinical study on about 600 patients who had been referred for biopsies. They then measured the concentration of zinc in the biopsy samples using X-ray-based elemental analysis and compared the results with zinc levels in the blood. The results, which were published in The Prostate, not only showed that lowered levels of zinc in malignant prostate tissue could be detected at very early stages of the disease, they also showed, for the first time, that zinc depletion is positively correlated with tumor aggressiveness: The more aggressive the tumor, the greater the zinc depletion. In contrast, the benign tissue surrounding the tumor contained normal zinc levels. These three findings imply that mapping zinc in the prostate might be a useful way of pinpointing the exact location of a tumor and gauging its aggressiveness.
 
In a subsequent study, published in Physics in Medicine and Biology, the researchers tested whether images of prostatic zinc concentrations could potentially be used in a non-invasive X-ray-screening method. The method was assessed on the basis of computer-simulated images, using zinc concentration values obtained from the clinical trials. By analyzing the images and revealing the regions of depleted zinc, the researchers could not only classify an area as cancerous or benign but also determine the aggressiveness of the cancer as well as its dimensions and location within the prostate gland.
 
On the basis of these results, the team has launched an R&D program to promote the development of a non-invasive, transrectal probe that will generate zinc maps of the prostate gland through X-ray imaging.
 
Chechik: “Although it’s a few years away from production, we hope that the probe will be able to grade the aggressiveness of the tumor as well as indicate whether the cancer might have proliferated to areas outside the prostate gland. This information will help physicians decide whether a biopsy should be performed and significantly increase the sensitivity and accuracy of the biopsy.” Breskin: “The method is designed to help, in the future, in clinical decision making, as well as to be used to guide focal treatments. At the post-treatment stage, the probe could be an effective, non-invasive follow-up tool.”
 

Prof. Amos Breskin’s research is supported by the Helen and Martin Kimmel Center for Archaeological Science. Prof. Breskin is the incumbent of the Walter P. Reuther Chair of Research in Peaceful Uses of Atomic Energy.

(l-r) Marco Cortesi, Dr. Rachel Chechik, Prof. Amos Breskin and Dr. Sana Shilstein. Using medical intelligence
Life Sciences
English

Saving Up Sunshine

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Prof. Igor Lubomirsky. New energy: Turning excess CO2 into fuel

 

 

 

 

 

 

 

 

 

 

 

 

One of the unsolved technical challenges holding back the global use of such renewable energy resources as solar or wind is that they’re not always able to deliver power when and where it’s needed. There’s plenty of sun and wind – enough to run all the factories, computers and air conditioners in the world; but supplying that energy on demand is still problematic.

If only we had a way to save the sun’s energy for a rainy day. Coal, for instance, is a form of stored energy: It can be burned at will to create steam, which, in turn, produces electricity. In contrast, solar panels and windmills convert sunshine and wind directly to electricity – useful for powering our homes, but hard to stockpile. Many solutions have been proposed, but most (oversized batteries, for example, or pumping large quantities of water uphill) remain expensive, unwieldy or impractical in other ways. One promising avenue that scientists have been exploring is that of converting the energy obtained from the sun or wind into a form that can be stored, transported and burned at a later date. In the 1980s and 1990s, Weizmann scientists began pursuing methods for storing solar energy in chemical bonds, using highly concentrated solar energy created in the Institute’s solar tower (thermochemical heat pipe).

Now, Prof. Igor Lubomirsky of the Institute’s Materials and Interfaces Department in the Faculty of Chemistry has come up with a novel alternative for converting solar energy into fuel. What’s more, his method is comparatively inexpensive, produces no environmentally hazardous waste and is very efficient. Rather than coal (which takes millions of years to be created and emits pollutants when burned), the new method produces carbon monoxide (CO) – a non-corrosive gas that can be burned directly in turbines or generators, or converted on-site into liquid fuel. Although it’s toxic in high concentrations, CO has been used for over a hundred years as an intermediate chemical product; tens of millions of tons are synthesized each year from coal or wood in one of the most developed of industrial processes.

In Lubomirsky’s approach, the CO is generated from CO2 in a relatively straightforward chemical process using a setup that’s something like a large, hot battery. Inside a special cell, a chemical compound is heated to around 900°C and an electric current is passed through the compound. When CO2 is continuously fed into the cell, the result is pure CO and oxygen.

“CO could be produced right at the smokestack of a power plant or other CO2 source,” says Lubomirsky, “so the greenhouse gases released from the plant would be removed and recycled before they have a chance to hit the atmosphere. The metal used in the process is off-the-shelf titanium, which is many times cheaper and more available than such precious metals as platinum that are often used in similar devices.” Other advantages of the method include a thermodynamic efficiency of over 85% (not counting the energy needed to heat the system), which is almost unheard of in the world of energy conversion, and the ease of transporting and burning CO.

Lubomirsky: “In the future, this method might be used to harvest solar or wind energy in places where it’s plentiful, convert it to CO and store or convert it into a liquid fuel such as methanol. This research is 100% the fruit of Weizmann Institute scientists and resources, especially the Institute’s Alternative Energy Research Initiative (AERI), which supports a number of important research projects in the field.”

Yeda, Ltd., the technology transfer arm of the Weizmann Institute, has applied for a patent for the method, and preliminary tests are planned for the near future.

Prof. Igor Lubomirsky’s research is supported by the Nancy and Stephen Grand Research Center for Sensors and Security; the Phyllis and Joseph Gurwin Fund for Scientific Advancement; Yossie Hollander, Israel; Martin Kushner Schnur, Mexico; Rowland Schaefer, New York; and the Wolfson Family Charitable Trust.

Freeze and Heat

Can one freeze water by heating it? In research that recently appeared in Science, Lubomirsky, working with then research student David Ehre and Prof. Meir Lahav, demonstrated that water can turn solid at different temperatures, depending on the electric charge of the surface underneath. By creating conditions for the charge to be reversed, they found that ice could even form as the surface heated up.

The experiment was based on a long-standing conjecture that an electric charge could promote freezing by causing the water molecules to align with the charge. When water freezes at 0° Celsius, the ice crystals start to coalesce around dust particles or other impurities. But so-called super-cooled water, such as that in high clouds, can stay liquid well below the freezing point if nothing sets off crystallization. Testing the theory was problematic, however, as materials that hold a charge – mostly metals – also act as nuclei for ice formation.

The team solved the problem by placing the water on a special surface made of pyroelectric crystals; these can carry a charge when heated or cooled, but do not provide a nucleus for ice crystals. To their surprise, they found that whereas on a positively charged surface, the water froze at -7°C and on the uncharged surface at -12.5°C; on the negatively charged material, it only turned to ice at -18°C. When they put liquid water on the negatively charged surface, the water turned to ice when that surface was heated from -11°C to -8°C.

Prof. Igor Lubomirsky
Environment
English

Scents and Sensibility

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Prof. Noam Sobel and Yaara Yeshurun. Remembering the smell
 
 
From Proust’s madeleines to the overbearing food critic in the movie Ratatouille who’s transported back to his childhood by the aroma of stew, artists have long been aware that some odors spontaneously evoke strong memories. Why do smells figure this way in the memory?
 
Graduate student Yaara Yeshurun, together with Profs. Noam Sobel and Yadin Dudai of the Weizmann Institute’s Neurobiology Department, thought that the key might lie not necessarily in childhood but rather in the first time a smell is encountered in the context of a particular object or event. In other words, the initial association of a smell with an experience will somehow leave a unique and lasting impression in the brain.
 
To test this idea, the scientists devised an experiment: First, in a special smell laboratory, subjects viewed images of 60 objects, each presented simultaneously with either a pleasant or an unpleasant odor generated by a machine called an olfactometer. Next, the subjects were put in an fMRI scanner to measure their brain activity as they reviewed the images they’d seen and attempted to remember which odor was associated with each. The whole test was then repeated – images, odors and fMRI – with the same images but different odors accompanying each. Finally, the subjects came back a week later to be scanned in the fMRI again. They viewed the objects one more time and were asked to recall the odors they associated with them.
 
The scientists found that after one week, even if the subject recalled both odors equally, the first association revealed a distinctive pattern of brain activity. The effect was seen whether the smell was pleasant or unpleasant. This unique representation showed up in the hippocampus, a brain structure involved in memory, and in the amygdala, a brain structure involved in emotion. The pattern was so profound, that just by looking at the brain activity within these regions following the initial exposure, the scientists could predict which associations would come up a week later. To see if other sensory experiences might share this tendency, the scientists repeated the entire experiment using sounds rather than smells; they found that sounds did not arouse a similar distinctive first-time pattern of activity. In other words, these results were specific to the sense of smell. “For some reason, the first association with smell gets etched into memory,” says Sobel, “and this phenomenon allowed us to predict what would be remembered one week later, solely on the basis of brain activity.”
 
Yeshurun: “As far as we know, this phenomenon is unique to smell. Childhood olfactory memories may be special not because childhood is special, but simply because those years may be the first time we associate something with an odor.”

 
Prof. Noam Sobel’s research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the J&R Foundation; the Eisenberg-Keefer Fund for New Scientists; and Regina Wachter, New York, NY.
Prof. Noam Sobel and Yaara Yeshurun.
Life Sciences
English

Color It Pink

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(l-r) Dr. Asaph Aharoni, Dr. Ilana Rogachev, Tal Mendel and Dr. Avital Adato. Love that pink

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Banana yellow, lime green, plum purple: Our first association with a fruit is often its enticing color. But for plants, color is about much more than aesthetics. The purple compounds in grape skins, for instance, protect the fruits from ultraviolet radiation, pests and diseases. Humans also benefit from eating these substances – known as flavonoids – as they have all sorts of antioxidant and disease-preventing properties. They not only improve our health; these compounds and their derivatives tempt us into eating the fruit by helping it develop a pleasing aroma when it ripens.
 
Mutations in genes for color are prized – they produce purple peppers, yellow watermelons, pink tomatoes. Pink tomatoes lack a yellow pigment that’s found in normal red tomato skins. They’re also a bit sweeter than the average red tomato, making them popular, especially in the Far East. For this reason, breeders and agricultural firms have taken an interest in them.
 
Pink tomatoes have also caught the attention of Dr. Asaph Aharoni of the Institute’s Plant Sciences Department. Aharoni and his team focus on the thin outer layer of a plant – the cuticle – which is mainly composed of fatty, wax-like substances. In tomatoes, these substances are joined by large amounts of flavonoids, which both help to protect the fruit and add a strong yellow tint to the color. The cuticle of the mutant tomato, in contrast, is a delicate, translucent pink. In research that appeared in PLoS Genetics, Aharoni, Drs. Avital Adato and Ilana Rogachev, and research student Tal Mendel discovered the gene that makes the regular tomato yellowish-red and the mutant tomato pink.

Aharoni’s lab has a system that’s unique in Israel, and one of only a few in the world. Using a combination of molecular, chemical and analytical methods, he and his research team are able to identify hundreds of metabolites – active compounds in plants – and create a comprehensive profile of all the substances produced in the mutant plant, which is then compared with that of normal plants.

The scientists found that the difference between pink and red tomatoes goes much deeper than an absence of yellow pigment in the skin: They identified around 400 genes whose activities were radically different in the mutants – at least twice as intense or less than half of normal. The mutation influenced the production of a number of substances in the flavonoid family, both in the cuticle and in the flesh of the fruit. In addition, pink tomatoes contain less lycopene – a red pigment and powerful antioxidant known to have a number of health benefits. The pink cuticle is thinner than the red one but less flexible, due to alterations in the composition of the fatty substances.

The gene mutated in the pink tomato, known as SIMYB12, is a sort of “master switch” that regulates an entire network of other genes, overseeing the production and quantities of many metabolites in the tomato fruit. Aharoni: “Researchers can now use this gene as a ‘marker’ to reveal the future color of the fruit early on – months before the plant flowers and bears fruit. This might greatly accelerate the creation of new varieties, a process that normally can take 10 years or more.”

Dr. Asaph Aharoni’s research is supported by the De Benedetti Foundation-Cherasco 1547; and the Willner Family Foundation. Dr. Aharoni is the incumbent of the Adolpho and Evelyn Blum Career Development Chair of Cancer Research.

 
 
 
 
 
 
 
 
 
Dr. Arieh Moussaieff and the frankincense source
 

Color It Mellow

 

The rabbis who wrote the Talmud around 1,500 years ago knew about the unique properties of frankincense (levona in Hebrew). They sanctioned adding a pinch of the aromatic tree resin to the wine of a condemned criminal, to “benumb his senses.” Research by Dr. Arieh Moussaieff, a postdoctoral fellow in Dr. Asaph Aharoni’s lab, shows that this resin, gathered for thousands of years from trees of the genus Boswellia, contains compounds that relieve depression and anxiety.
 
Moussaieff first encountered frankincense while researching a plant-based remedy made in a monastery in Jerusalem’s Old City. In folk medicine, the resin is believed to have anti-inflammatory properties, and to ease digestive and respiratory problems. But frankincense is most widely used as incense in religious ceremonies ranging from ancient Egyptian, Jewish and Christian rites to Chinese and Indian rituals.
 
In his doctoral work at the Hebrew University of Jerusalem, Moussaieff isolated the active compounds in the resin. When tested on mouse models of human head injury, he found that some of these substances provide protection for the nervous system. He later noted the resin’s antidepression and antianxiety properties and, investigating further, found that they act on a previously unknown pathway in the brain that regulates emotion. These findings not only help explain the ubiquity of frankincense in religion, they also hint that the active compounds might be used in the future to treat any number of neurological diseases, from Alzheimer’s and Parkinson’s to depression.
 
Moussaieff’s current research involves investigating how the resin is produced in the tree. The active compounds are, at present, too complex to manufacture on a marketable scale, and he hopes that uncovering the natural mechanisms of frankincense creation in the tree will point the way toward methods of producing it efficiently.
 
l-r) Dr. Asaph Aharoni, Dr. Ilana Rogachev, Tal Mendel and Dr. Avital Adato
Environment
English

Balancing the Budget

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Dr. Eyal Roteberg and Prof. Dan Yakir. Hot forest

 

 

 

 

 

 

 

 

 

 

 

The simple formula we’ve learned in recent years – forests remove the greenhouse gas CO from the atmosphere, therefore forests prevent global warming – may not be quite as simple as we thought. In research recently published in Science, Weizmann Institute scientists have shown that forests can directly absorb and retain heat, and in at least one type of forest these effects may be strong enough to cancel out a good part of the benefit of lowered CO2.

Semiarid forests cover more than 17% of the earth’s land surface. Over the past 10 years, the Yatir research station at the edge of the Negev Desert has provided a comprehensive picture of the processes taking place in them. Forests counteract the “greenhouse effect” by removing heat-trapping CO2 from the atmosphere and storing it in living trees. Prof. Dan Yakir of the Environmental Sciences and Energy Research Department of the Institute’s Faculty of Chemistry has found that semiarid forests, though not as luxuriant as the temperate forests farther north, are surprisingly good carbon sinks – better than most European pine forests and about on a par with the global average.

But forests do more than just store CO2, and Yakir, together with Dr. Eyal Rotenberg, decided to look at the “total energy budget” of a semiarid forest. The first hint that other processes might be counter-acting the cooling effect of CO2 uptake came when they compared the forest’s albedo – how much sunlight is reflected from its surface back into space – with that of the nearby open shrubland. They found that the dark-colored forest canopy had a much lower albedo, absorbing quite a bit more of the sun’s energy than the pale, reflective surface of surrounding areas.

Next the researchers looked at the mechanisms for “air conditioning” within the forest itself. To cool down, trees in wetter areas use water-cooling systems: They open pores in their leaves and simply let some of the water evaporate. But the semiarid pine forest is not built for evaporation. The scientists found that it uses an efficient alternative air-cooling system. Here, the air in the open spaces between the trees comes into contact with a large surface area, and heat can be easily transferred from the leaves to the air currents. But this efficient, semiarid air-cooling system leads to a reduction in infrared (thermal) radiation out into space. In other words, while the semiarid forest can cool itself well enough, it both absorbs more solar energy (through the albedo effect) and retains more of this energy (by suppressing the emission of infrared radiation). Together, these effects turned out to be stronger than the scientists had expected. “Although the numbers vary with location and conditions,” says Yakir, “we now know it will take decades of forest growth before the ‘cooling’ CO2 sequestration can overtake these opposing warming processes.”

Yakir and Rotenberg asked one more question: If planting semiarid forests can initially lead to warming, what happens when the opposite process – desertification – takes place? By applying what they had learned to existing data, they found that desertification, instead of hastening global warming as is commonly thought, actually mitigates it, at least in the short term. By reflecting sunlight and releasing infrared radiation, the desertification of semiarid lands over the past 35 years has slowed global warming by as much as 20%, compared with the expected effect of the CO2 rise. And in a world in which desertification is continuing at a rate of about 6 million hectares a year, that news might have a significant effect on how we estimate the rate and magnitude of climate change.

Yakir: “Overall, forests remain hugely important climate stabilizers (not to mention the other ecological services they provide), but there are tradeoffs, such as those between carbon sequestration and surface radiation budgets, and we need to take these into consideration when predicting the future.”

Prof. Dan Yakir’s research is supported by the Avron-Wilstaetter Minerva Center for Research in Photosynthesis; the Sussman Family Center for the Study of Environmental Sciences; the Cathy Wills and Robert Lewis Program in Environmental Science; and the estate of Sanford Kaplan.

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FLUXNET tower in the Yatir forest
 
Ten years ago, the Weizmann Institute’s Environmental Sciences and Energy Research Department received a grant to erect a research station in the Yatir Forest to be part of FLUXNET – an international chain of such stations that gathers information on carbon dioxide, water and energy exchange in forests around the world.
 
“Once we got the approval,” says Prof. Dan Yakir, “We had to erect a 20-meter-tall tower, on a shoestring budget. We went to a junkyard in Tel Aviv and salvaged old steel supports, which we then loaded onto a truck and drove down to the Dead Sea, where a welder straightened and painted the sections. Despite its origins, our tower and its measurement systems met all the European standards, and it’s still standing strong after 10 years.”
 
The Yatir site is FLUXNET’s oldest functioning station in a semiarid forest. About one hundred sensors take measurements 10 times a second, around the clock; six doctoral theses, seven postdoctoral papers and 27 scientific papers based on the data have been produced so far. The station will soon expand both its area and its research capabilities with a new mobile lab.
 
(l-r) Dr. Eyal Rotenberg and Prof. Dan Yakir. Staying cool
Environment
English

A Prize for Crossing Boundaries

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skeletal proteins prgressively constrict an artificial membrane
 
 

 

 

 

 

 

 

 

 

 

A doctoral student with a degree in physics, who conducts research on biological systems in the Faculty of Chemistry, has received an award given by the Faculty of Mathematics. To Roie Shlomovitz, a student in the group of Prof. Nir Gov of the Chemical Physics Department and the 2010 recipient of the Lee A. Segel Memorial Prize in Theoretical Biology, this makes perfect sense. Prof. Segel, a member of the Weizmann Institute’s Mathematics and Computer Science Faculty for many years who passed away in 2005, was one of the first to cross the boundaries between the disciplines of mathematics and the life sciences, showing that mathematics could be used to describe the dynamics of biological systems and teaching biologists to think “mathematically.” “My work fits right in with Segel’s approach,” says Shlomovitz.

Shlomovitz and Gov investigate proteins that form the cell’s internal skeleton. These proteins – actin and myosin – make up the fibers that enable our muscles to contract and are involved in cell movement and cell division. When a cell moves, actin filaments gather on the leading side, forming a bulge that propels the cell onward. In cell division, actin and myosin proteins create a ring encircling the cell’s midriff, squeezing the membrane tightly and pinching it in two.

What causes these proteins to push the cell membrane outward in one case and constrict it in another? How do they “know” when and where to apply pressure? To address such questions, Shlomovitz and Gov observe what happens to these proteins in cells, turn the data into mathematical models and, finally, test the predictions of their models in such biological systems as yeast. According to their model, actin and myosin proteins get their directions from the shapes of molecules in the cell’s membrane. When the cell is about to move, the membrane points the way by exaggerating its outward curve on one side. The convex membrane molecules “invite” the actin to gather round; large amounts of these molecules and the actin flock to the site to drive the edge forward. In the early stages of cell division, on the other hand, the membrane’s center takes on an inward curve. Investigating bacterial proteins, the researchers found that concave curves attract these proteins, as well: A circular network of actin and myosin marks the division line.

The mathematical model they developed borrowed an equation from physics that describes the free energy of a system. Using this equation, they calculated the distribution of proteins in the membrane and revealed how this distribution relies on the membrane’s shape. The researchers showed exactly how the bowed segment induces the proteins to encircle the membrane right at the center, how the growing inward bend of the membrane continuously attracts more proteins to the spot to increase the constriction, and how the distance between one protein and the next determines whether they’ll become a part of the tightening band or form separate rings.

Their model not only predicted the behavior of these proteins on artificial membrane bulges and indents; an experimental group in Taiwan found it could also explain the wavy shapes of living cell membranes. Shlomovitz: “We describe the complex biological processes occurring within a single cell by constructing chemical and physical models. Mathematics is the ‘language’ we use to analyze them.”


Prof. Nir Gov’s research is supported by the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly.

 
Distribution of skeletal proteins in an artificial membrane resembling a long bacteria: The spontaneous curvature of the proteins (purple) drives them to move together to form rings that coalesce, increasingly constricting the membrane
Chemistry
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Outside Influences

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The whole is more than the sum of its parts

– Aristotle, Metaphysics

Zelzer and his team investigate joint development

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The body is a sort of self-contained society, governed by the coordinated efforts of its individual organs and components. But what about the individual organs themselves? Are they “self-governing” – able to develop independently of the whole – or do they rely on outside influences to develop and function? In other words, do different growing tissues interact, helping to sculpt one another as they take shape?
 
In two recently published papers, Dr. Elazar Zelzer and his colleagues in the Weizmann Institute’s Molecular Genetics Department present mounting evidence that tissue interactions are a fairly influential factor in the shaping of organs.
 
In the formation of joints, for example, the different tissues develop from a pool of uncommitted cells called progenitor cells which, as they “grow up,” turn into the various cell types that constitute the mature joint. So, for instance, the fate of some cells in the “joint pool” is to grow into tough cartilage, while others become soft synovium (joint capsule) tissue. Keeping progenitor cells committed to their designated fate is a prerequisite for correct organ development; how they are kept on course is a key question. The answer, Zelzer believes, lies in outside influences.
 
One hint comes from the kicks and prods that expectant mothers experience during pregnancy: It’s long been recognized that their babies are not merely practicing to become the next Bruce Lee; but in fact, such movements play a fundamental role in normal development. When fetal movement is restricted, as in fetal akinesia deformation sequence (FADS), the result is various disorders, among them arthrogryposis multiplex congenita (AMC), which is characterized by multiple joint abnormalities. However, the exact relationship between muscular movement and joint formation remained unknown.
 
To shed light on the matter, former postdoctoral fellow Dr. Joy Kahan, who initiated the study, and M.Sc. student Yulia Schwartz started working backwards to try to identify the developmental checkpoint at which joint malfunctions first occur. They took four mutant strains of mice – three that don’t form any muscle in the limbs whatsoever and one that forms muscle, but is paralyzed. They genetically labeled the various progenitor cells so they could trace the events.
 
The team found, as they reported in Developmental Cell, that in all four scenarios, the ability to form functional joints was lost. Why should missing or paralyzed muscle affect joint development? Upon further analysis, they discovered that in the absence of muscle contractions, the joint progenitor cells’ critical “puberty” stage is disrupted: Instead of maturing into the joint-forming cells they were destined to become, these cells experience a sort of “identity crisis” and grow up to be cartilage cells
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“Through our findings that muscular contraction ultimately regulates joint cell fate and formation, we have provided, for the first time, in vivo evidence highlighting the important connection between embryonic movement and organ development, showing that it’s not solely dependent on intrinsic factors,” says Zelzer.
 
Another example of tissue interaction can be seen in the developing vascular system. Since blood vessels supply all the other organs with all their oxygen and nutrient needs, it’s vital that their development be synchronized. The question is, does the developing organ regulate blood vessel growth or vice versa? Or are they all innately programmed to develop independently? Zelzer’s Ph.D. student Idit Eshkar-Oren turned to the skeletal system to try to provide some answers.
 
During the initial stages of embryonic development, the limbs are populated with blood vessels throughout. As development proceeds, the skeleton secretes anti-growth factors, causing the blood vessels to regress and making way for the growth of cartilage, which is, in turn, later replaced by bone. It would make sense, then, to find fewer new blood vessels near the skeleton and more farther away, where the anti-growth signals are weaker. Yet, this is not the case: Flanking the bony growth are areas rich in blood vessels. What regulates this unlikely patterning? Surprisingly, both processes – vessel growth and vessel regression – are governed by the skeleton. In research published in Development, the team showed that not only does the skeleton secrete negative growth factors, but it also secretes a well-known factor (VEGF) that encourages blood vessel growth. In this way, the scientists believe, the skeleton compensates for the blood vessel retreat, ensuring a sufficient supply of nutrients and oxygen nearby, even as the bones themselves are disconnected from the blood system.
Zelzer: “The evidence we have accrued from our studies clearly suggests that tissue interactions are an important factor governing embryonic organ development. Because the skeletal system is a central organ system associated with a large variety of congenital diseases and malformations, shedding more light on its embryonic development may hopefully improve our ability to treat and prevent such conditions.”
 
 
Dr. Elazar Zelzer’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research; the Kirk Center for Childhood Cancer and Immunological Disorders; the David and Fela Shapell Family Center for Genetic Disorders Research; and the estate of Rubin Feryszka. Dr. Zelzer is the incumbent of the Martha S. Sagon Career Development Chair.
 
Mouse embryo skeleton showing sites of initial bone formation (stained red) and cartilage (green and blue), which will later be replaced by bone
 

 

 

 

 
Mouse embryo skeleton showing sites of initial bone formation (stained red) and cartilage (green and blue), which will later be replaced by bone
Life Sciences
English

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