Prof. David Cahen (right) and Dr. Leeor Kronik (left): Keeping track of wandering atoms
Self-healing is normally the province of living creatures, but now a Weizmann Institute-led research team has discovered that it can occur in semiconductors as well. This finding may help create better solar cells and other electronic devices.
Solar cells, which convert sunlight into electricity, could offer a perfect way of using solar energy. But unfortunately, such devices can be built only from materials that are either very expensive or unstable. One type of experimental semiconductor could provide a solution. Copper indium gallium diselenide is inexpensive because only very small amounts of it are needed. It is also extremely stable, a characteristic that has long baffled the scientific community because it appears to defy common sense: Copper indium gallium diselenide is so complex that one would expect it to be easily disrupted, yet it manages to survive intact for long periods of time under harsh conditions, including those present in outer space.
Now this mystery has been solved by an international team headed by Prof. David Cahen of the Weizmann Institute's Materials and Interfaces Department, working with consultant Dr. Leeor Kronik of Tel Aviv University and colleagues from France's CNRS and Germany's Stuttgart University.
Their discovery is based, among other things, on a study in which crystals of a related material, copper indium diselenide, were examined using high-energy X-rays. That study, conducted by Cahen and his colleagues at the European Synchrotron Radiation Facility in Grenoble, showed that in some cases the bonds between certain atoms of copper indium diselenide can be broken relatively easily.
Cahen's group also showed that copper atoms can move inside these semiconductor crystals. This finding was most surprising: Such movement is uncommon in solid, nonliving materials and is extremely unusual in materials used in electronic devices, where atomic mobility is viewed as ana?thema. Moreover, seeing it in a semiconductor known for its stability was particularly unexpected.
Atomic checkers
Another even more surprising finding provided the explanation for the material's mysterious stability. Once some atomic bonds have been broken, the copper atoms, which are capable of moving throughout the crystal, wander around until they reach the damaged spot and undo the effects of the damage. This "self-repair" mechanism stems from the material's tendency to try to stay close to equilibrium.
"Now we understand how solar cells made of copper indium gallium diselenide manage to survive and function effectively in hostile environments such as those encountered by satellites: Once damaged ? for example by radiation ? this 'smart' material simply 'heals' itself and restores its previous function," Cahen says.
This research may lead to more extensive use of copper indium gallium diselenide and help in designing other self-stabilizing materials.
How does DNA protect itself in conditions of acute starvation or environmental assault? Prof. Avi Minsky of the Weizmann Institute's Organic Chemistry Department has found that, in bacteria, DNA's answer is to "get organized."
During various conditions of stress, Minsky discovered, bacterial DNA becomes remarkably organized into a tightly packed crystalline structure, allowing the bacteria to better withstand environmental stress. "In natural environments, bacterial life alternates between short periods of feast and long periods of famine," says Minsky. "To survive, bacteria have evolved complex mechanisms that allow them to protect themselves during starvation and stress, as well as to resume growth very rapidly when conditions improve. The ordered DNA structure may represent the ultimate mode of protection."
The Weizmann team revealed further that the highly ordered structure is mediated by a protein called Dps, which strongly binds DNA, increasing its stability. The Dps protein, characterized by Prof. Roberto Kolter's group at Harvard Medical School with which Minsky collaborates, is present at high levels in stressed cells. Within this ordered and tightly packed DNA-Dps structure, the DNA is very effectively protected against various assaults.
The scientists used X-ray and electron microscopy techniques, which are currently being employed to uncover the molecular structure of the complex between the Dps protein and the DNA. Says Minsky: "We are currently investigating the actual signal that triggers the formation of the crystalline structure when the organism is subjected to starvation or stress, and the signal that causes its fast disappearance once stress is eliminated."
Stress protein under the microscope
Other than providing important information on how DNA could be protected, the findings may one day contribute to the development of more general methods against bacterial diseases. In addition, if a link is found between the mechanisms allowing bacteria to survive under stress and those that render bacteria resistant against various chemical agents, chemotherapy could be efficiently used against pathological bacteria that have become resistant to other methods.
Minsky: "Order is generally considered to be incompatible with life. However, in living systems exposed to severe environmental assaults, ordered assemblies may confer an efficient means for wide-range protection. Indeed, ribosomes in brain cells of people suffering from dementia were found to form crystalline organizations. Moreover, DNA in sperm cells is highly ordered. We have now found this to be true in bacterial DNA as well and are trying to understand how general and significant the correlation is between order and survival."
Accordingly, the Weizmann team has recently begun to study the correlation between the organization of DNA and fertility in human sperm cells.
Whether sniffing flowers, freshly baked bread, or the fumes of a passing automobile, the human olfactory system is an amazing scent-sleuth, capable of distinguishing between millions of different smells. Now Weizmann Institute scientists have revealed one of the secrets behind this impressive ability.
To produce a response in the olfactory system, the molecules of a particular substance must penetrate the nose. There they encounter olfactory receptors -- specialized proteins protruding from the surface of nerve cells in the inner lining of the nose. When an odor molecule lands on a receptor, the nerve cell dispatches an electrical signal to the brain, which processes this information and identifies the smell.
Theoretically, one could imagine that for every odor molecule there might be a different receptor, determined by specific genes. However, even if there were only, say, 10,000 discernible smells, this would mean that fully one-tenth of humankind's hereditary code (comprising some 100,000 genes) would have to be dedicated to smell receptors -- obviously impossible. If, on the other hand, unique receptors do not exist for each individual smell, how does the olfactory system make sense of such a vast variety of odors?
Several years ago Prof. Doron Lancet of the Weizmann Institute's Molecular Genetics Department proposed that olfactory receptors are "generalists"; they have the capacity to bind with several odor molecules. Conversely, each odor molecule can bind with a range of potential receptors. The intensity of the binding varies, depending on the quality of the fit. Thus a given odor molecule might bind to receptor A with great intensity, but to receptor B with only mild intensity, and so forth. The pattern of different bonds creates a unique "fingerprint" that the brain can understand as a particular smell. The signaling mechanism used by different receptors is the same; it is the brain that tells the signals apart by knowing which nerve cell it is coming from.
This model grew out of Lancet's hunch that the olfactory system might function in a way similar to the immune system, which also needs to recognize a vast array of molecules. To that end, the immune system produces a large set of antibodies capable of trapping a wide variety of invaders.
Now, Lancet and doctoral student Yitzhak Pilpel have provided new evidence on how the "generalist" model works at the structural level. They have also shown that the similarity between olfactory receptors and antibodies may go a lot further than Lancet originally proposed.
By analyzing the DNA sequences of 200 olfactory receptors -- out of the estimated total of 500-1,000 in the olfactory system -- the scientists were able to model the receptors' 3-D structure. The results indicate that all olfactory receptors -- made up of some 300 amino acids -- have a similar structure: they contain large, framework-like regions that are shared by all members of the enormous family of recognition devices. In these regions there is a small, well-defined section made up of about 20 amino acids, which vary greatly from one receptor to another. That is precisely the site where an odor molecule can fit like a key into a keyhole.
These results reveal the secret of smell in all its simplicity and elegance: the "keyhole" region can easily be altered to accommodate a vast array of new odors while the "framework" of the receptor remains largely unchanged. This structural picture is very similar to what has long been known about antibody molecules: they contain a small, highly variable region geared to recognize a multitude of foreign invaders. Pilpel and Lancet believe that in the receptors for odor molecules they have uncovered the long-sought equivalent of the antibodies' "hyper-variable" region.
Other than providing us with information about one of the five senses, the Institute model of olfactory receptors, if supported by further studies, may prove useful for the development of new fragrances and flavors, and perhaps also in the design of artificial smell sensors.
At some point in its history, the keystone in the arch of the Byzantine church in the ancient city of Mamshit "slipped." This indicates that for a split second the arch was stretched open, causing the stone to drop: but then, a microsecond later, the arch was pressed back into position, trapping the stone in a slightly different position, as shown here. Only an earthquake is capable of causing such a shift. Hundreds of destruction patterns were identified and measured at Mamshit, indicating that the city underwent a devastating earthquake in the 7th century.
Earthquakes such as those that recently took place in Turkey and Greece demonstrate anew how powerless and insignificant man is in comparison to the forces of nature. This realization, and the attempts to avoid or reduce the damage caused by these forces may lead to regional cooperation in the Middle East. Initial steps in this direction are currently under way thanks to joint research by scientists form the Weizmann Institute, the Ramon Science Center, and the former Soviet Union.
Earthquakes can wipe whole cities off the map and change the course of history. Striking without warning and lasting only seconds, they leave a changed world in their wake. The ability to predict earthquakes could reduce the damage caused but, unfortunately, a reliable method of earthquake prediction has yet to be developed. The only certainty is that "As it once was, so shall it be again." That is to say, where earthquakes have occurred in the past, they may occur in the future. Therefore, accurate information about past earthquakes could help us plan for the future. For example, such information may dictate the need for safety regulations in the building codes of certain areas.
Modern geophysicists possess a fairly efficient database regarding quakes that have taken place since the beginning of the 20th century. However, reliable information about quakes occurring earlier is almost nonexistent. This may change soon, at least in the Negev region.
Prof. Emanuel Mazor of the Weizmann Institute's Environmental Sciences and Energy Research Department and his colleagues from the Ramon Science Center have examined evidence suggesting the occurrence of earthquakes in several ancient cities in the Negev. During the project, Dr. Alexander Becker, a member of the research team, suggested that Dr. Andre Korzhankov of the Kirgistan Seismological Institute be invited to join the team. Dr. Korzhankov often travels to the site of a quake immediately after the event, in order to record the patterns of destruction caused by the quake. The destruction patterns are indicated by the direction in which rocks and other objects fall. These patterns are then combined with the seismic data (the epicenter, its direction and magnitude), enabling calibration of the damage caused by the quake in comparison to its physical attributes.
The Israeli scientists suggested utilizing the information gathered by Dr. Korzhankov in order to "calculate backwards" various historic seismic events. In particular, they wanted to calculate the magnitude and epicenter of the quakes according to the destruction patterns found in these ancient Negev cities.
During the initial phases, the researchers focused on the ancient Nabataean city of Ovdat. They discovered that the city was demolished by earthquakes not once, as previously thought, but twice: during the 4th century, and again in the 7th. Strong quakes took place in the vicinity during the 9th and 18th centuries as well. The research team was surprised to discover that the epicenter of the 7th-century quake was Negev Mountain, rather than the Dead Sea Valley as earlier assumed. (The other quakes had their epicenter in the Valley, which is a part of the Syrian-African Rift.) Further research pinpointed the epicenter with greater accuracy as being in the vicinity of the Nafha region. The fact that one quake had its epicenter at Negev Mountain while three others were in the Dead Sea Valley testifies to a tectonic divergence between the mountain and the valley: The Rift Valley's tectonic pressure is relieved through numerous relatively small earthquakes, whereas the pressure that develops in the Negev Highland tends to be relieved in a single, powerful eruption.
Mazor thinks this information may encourage the Negev's industrial and urban development planners to take into consideration the region's tectonic nature. Says Mazor: "All peoples of this region have a vested interest in uniting to oppose the forces of nature, cooperating in the attempt to reduce as far as possible the destruction and suffering caused by earthquakes."
Layout of hewn stones in the wall of a Byzantine structure in the northern quarter of the ancient city of Shivta
Prof. Avi Levy and Vera Gorbunova: Plants do well in the evolutionary race
Rapid evolution is crucial for plants, embroiled as they are in a race for survival against formidable armies of fungi and bacteria.
"Plants evolve far more rapidly than mammals," says Prof. Avi Levy of the Weizmann Institute's Plant Sciences Department. "In the last 300 million years, only 4,000 mammalian species have evolved, in contrast to nearly 200,000 flowering plant species exhibiting a plethora of shapes, colors, and adaptations." Plants also demonstrate much greater variation than mammals in the amount of DNA per species. This genomic plasticity may be the plant's answer to a main grievance: unlike mammals, plants cannot flee in the face of danger; they have no choice but to stand their ground.
Levy and doctoral student Vera Gorbunova are investigating the underlying mechanisms that enable plants to be so versatile. They have found that compared to mammals, plants are highly prone to making "mistakes" when repairing damaged DNA. According to Levy and Gorbunova, the plant's error-prone repair strategies may actually be a blessing in disguise -- driving evolution forward by enhancing genetic variability.
"Plants tend to 'improvise'," says Gorbunova. "While their repair mechanisms seal a tear in the DNA, as do those of mammals and yeast, plants often 'rewrite' or 'delete' parts of the DNA in the process. The 'repaired' DNA is rarely identical to the original."
Genetic mutations occur regularly in all organisms as a result of environmental factors, including ultraviolet radiation and chemical toxins as well as, on a smaller scale, natural cell processes. Plant mutations are also influenced by jumping genes: during cell division these natural trailblazers are capable of jumping along the plant's DNA, randomly "knocking out" genes. Collectively, these mutagenic factors leave chaos in their wake, tearing the DNA and scrambling and deleting the genetic "letters" encoding an organism's traits.
Damaged DNA, if not repaired, can have disastrous consequences, especially in organisms that can develop cancer as a result. In plants, mutations can accumulate without the danger of their leading to cancer, since cells do not move within the plant body.
Fortunately, all organisms employ emergency repair "crews" designed to reverse or mitigate mutation-induced damage. Weizmann scientists have discovered that the mutation repair systems in plants are highly error-prone. In roughly 70% of cases, plants will simply "paste" torn DNA ends together, using a biological Scotch tape repair enzyme known as DNA ligase. This unsophisticated technique does not take into account the numerous complications that can occur.
"Unlike a precise cut made by scissors, DNA breaks generally result in the loss of entire pieces," says Gorbunova. In addition, exposed DNA ends are immediately scouted out and attacked by degrading enzymes. Therefore, simple rejoining via ligation generally leads to scrambling of the genetic code or loss of information.
Most interestingly, Levy and Gorbunova found that plants even "stitch" together diverse DNA from multiple sources. An apt analogy: Faced with a disastrous tear in their favorite jeans, plants generally sew the edges together; or they go for a dramatic fashion statement, introducing a different fabric or even a multicolored patchwork. In contrast, yeast takes the conservative route, replacing the missing fabric with identical material, Levy explains. Yeast does so by going to a homologous chromosome (genetic information is usually organized in pairs, termed homologous chromosomes, with one member of each pair originating from the female parent and the other from the male). According to the Weizmann team, when DNA in yeast is damaged, missing fragments are obtained by invading the homologous "partner" and copying an identical sequence. Plants also employ this strategy. But instead of choosing the problem-free homologous repair route, they commonly invade a nonidentical chromosome, leading to the insertion of unrelated DNA sequences.
Evolution in plants
These new insights into mutation repair pathways may lead to breakthrough genetic engineering efforts. "Today, it is nearly impossible to target a specific gene in order to effectively integrate beneficial traits into the plant genome," says Levy. "With yeast, in contrast, the 'designer' gene inserts itself directly into a homologous target." One prevailing idea is to introduce "blinders" into DNA modification pathways by "knocking out" or inhibiting the genes involved in non-homologous repair. "In this scenario, the DNA would have to use the alternative homologous machinery - thereby enabling precise integration and effective expression of beneficial traits."
"This phenomenon may provide a telling example of how error-prone DNA repair can generate useful traits," says Levy. The inherent approach is to absorb the loss of "bad" mutations -- an inevitable by-product of error-prone repair, so as to receive the "good" adaptability-enhancing sequences. The overriding strategy of plants for overcoming the problem of immobility may read as follows: become "star athletes" in the evolutionary race instead.
Prof. Itzhak Tserruya (center) with his team (left to right): Dr. Illia Ravinovich, Alexander Milov, Alex Cherlin, and Dr. Wei Xie
In a 2.4-mile-long tunnel built in the shape of a racetrack, scientists plan to race ion beams instead of horses. Two gold ion beams, traveling almost at the speed of light, will cross each other at four junctures, where they will collide head-on. The collision will produce a temperature ten thousand times that of the sun --a trillion degrees. Then, hopefully, as the particles fly out from the area of collision, the objective will be obtained: the re-creation of the big bang.
A team from the Weizmann Institute, headed by Prof. Itzhak Tserruya of the Particle Physics Department, is participating in the biggest and most extensive effort yet to answer one of the most fundamental questions of our existence: What happened after the big bang? Walking around the collider complex at the U.S. government's Brookhaven National Laboratory on Long Island with some of the leading scientists in this multi-pronged project (in which 430 scientists from 11 countries are participating), one can feel the almost childlike excitement of these scientists in the days leading up to the initial experiment. Reproducing the big bang is the kind of experience that generations of physicists before them could only dream of.
Fulfilling a critical role in the project, the Weizmann Institute scientists have designed and built 16 particle detectors; they will be used in the experiment to detect particles flying out of the collision area. With the highly sensitive and very strong, yet lightweight, detectors installed near the collision site, it will be possible to detect the interactions going on in the site and to identify the particles. The electronic circuitry of these detectors will identify the precise three-dimensional location of the particles as they come flying out from the collision. This information will then be combined with that from other detectors to calculate the energy of the particles and their subatomic identity.
Scientists theorize that quarks and gluons are the smallest, most basic building blocks of all matter. Microseconds after the big bang, in conditions of very high temperature and pressure, these quarks and gluons were in a special state of matter called quark-gluon plasma. According to the theory, this plasma state immediately began to cool down and then condensed into the nuclear particles with which we are familiar, protons and neutrons. Gradually, over time, these particles became atoms, which later combined into molecules, from which all forms of life eventually emerged.
Did you hear a big bang?
The experimental apparatus at Brookhaven used to re-create the big bang, is called a Relativistic Heavy Ion Collider (RHIC). The RHIC's accelerator is the most powerful in the world for use with heavy gold or lead ions used in nuclear experiments. By colliding two gold nuclei, the temperature will be so high and the pressure so intense, it is believed that the nuclei of the gold ions will go through a rapid transition phase and thus be transformed into the quark-gluon plasma. If this happens, a core component of the big bang theory will finally be proved.
The physicists involved in the Brookhaven project are used to being asked about the social value of the basic research they are doing. With obvious passion one of the researchers in the project explains to his visitors, as he leads them through the underground tunnels of RHIC, that pursuing answers to theoretical questions is the lifeblood of science. What motivates him, Tserruya, and others involved in the project is curiosity about the universe we live in. Without that curiosity and the directed energy that comes from it, there would be no Internet, no MRI, no high-speed trains, and no advances in cancer treatment. The applications of scientific discoveries create wealth and generate wonder about the power of technology. Curiosity about basic science, however, is the spark that lights the flame.
Prof. Michel Revel (right) and Prof. Tsvee Lapidot (left)
Weizmann Institute researchers have developed a molecule that allows blood stem cells -- the body's most primitive and most immature cells, which originate in the bone marrow -- to multiply without maturation in the test tube.
This achievement may improve bone marrow transplantation, in which stem cells are infused into a patient to replace defective or malignant marrow. The study may also advance gene therapy research.
The new molecule was developed by Prof. Michel Revel and Dr. Judith Chebath of the Molecular Genetics Department, and its effects on blood stem cells were studied by Dr. Tsvee Lapidot and graduate students Orit Kollet and Ronit Aviram of the Immunology Department.
Most stem cells originating in the bone marrow mature daily to replenish our blood. A small number of stem cells, however, survive and renew themselves without maturation, thanks to a natural mechanism in which the cells receive signals from molecules called cytokines. Among these molecules is interleukin-6, a chemical messenger discovered in the 1980s in Revel's laboratory. In order to respond to interleukin-6, the stem cells form a cluster with this cytokine, consisting of a receptor molecule on their surface known as gp130 and another molecule called the interleukin-6 receptor, which the cells pick up from surrounding fluids.
In contrast, when isolated in the test tube, the stem cells do not efficiently form the cluster with interleukin-6 and fail to survive: They start to mature into various types of blood cells and lose their original properties within three to five days. This has caused the greatest difficulty in studying stem cells and using them for therapeutic purposes
In their study, Weizmann Institute scientists used a so-called "chimera" recombinant molecule, consisting of interleukin-6 and its receptor fused together. The "chimera" proved extremely efficient in spurring on the formation of clusters with gp130 on the surface of stem cells purified from human bone marrow or from human umbilical cord blood. When the chimera was added to isolated stem cells together with other cytokines, the cells were able to survive in the test tube for two weeks and their numbers increased significantly. In the future, this new approach may make it possible to keep the stem cells proliferating without maturation for much longer periods.
By transplanting the treated human stem cells into mice with severe combined immunodeficency, the scientists verified their ability to repopulate the bone marrow and produce all types of blood cells, demonstrating that the stem cells had indeed remained immature. A large increase in the efficacy of transplantation was observed with the stem cells that had received the chimera treatment compared with untreated cells.
If the Weizmann Institute molecule is adopted for clinical use, allowing stem cells to survive longer and increasing their numbers, the success of bone marrow transplantation can be improved. Such transplantation is currently used to treat an increasing number of diseases, including different types of leukemia and cancerous tumors, several blood cell disorders and even autoimmune diseases such as multiple sclerosis.
recmobinant molecule for stem cells
The Institute study may also provide a boost to gene therapy research by giving scientists a larger window of opportunity for inserting genes into human stem cells maintained in the laboratory. If scientists manage to do that, they may be able to develop gene therapy for various genetic disorders such as thalassemia, severe combined immuno?deficiency, Gaucher's disease, and other disorders. Since transplanted stem cells repopulate the bone marrow of the recipient and daily produce billions of blood cells, inserting a gene in these cells prior to transplantation would ensure a steady supply of the protein made by this gene, compensating for the genetic defect causing the disease.
The Institute scientists collaborated with researchers from the Bone Marrow Transplantation Center at the Hadassah University Hospital in Jerusalem, from the Kaplan Hospital in Rehovot and from the Jackson Laboratory, Bar Harbor, Maine.
For the proteins in our body there's not much room for mercy. If old or damaged proteins were allowed to accumulate in a cell, it would soon become useless. Thus, a sophisticated recycling system quickly breaks down deficient proteins. But, as has recently been found, healthy proteins, including proteins that inhibit cancer, often meet the same fate. This is due to a molecule that, together with its helpers, serves as a "death tag." Weizmann Institute scientists have identified one of the sinister helpers involved in the nefarious work of breaking down cancer-preventing proteins.
Twenty years ago, Profs. Abraham Hershko and Aharon Ciechanover of the Technion Medical School discovered an enzyme system dedicated to breaking down proteins in the cell. This system contains many kinds of enzymes, each responsible for seeking out and destroying a specific group of proteins, according to their three-dimensional structure. The scientists discovered the existence of a small protein called ubiquitin, which functions as a sort of "death tag." Ubiquitin is attached to the damaged protein by enzymes, and it then "calls out" to the various wrecking enzymes. After these complete their work, the "death tag" is released and returns to a cache in the cell.
It has recently come to light that the same system is also responsible for breaking down functioning proteins when their level rises above that desired in the cell. Prof. Moshe Oren of the Weizmann Institute's Molecular Cell Biology Department is studying the p53 protein, product of the p53 gene, whose proper functioning inhibits the development of tumors. Apparently over 50% of cancers in humans are caused by changes in the p53 gene that lead to the protein's dysfunction. In normal cells the amount of p53 protein is minute; but the moment the cell is exposed to a process that may lead to mutation and thence to the development of cancer, the amount and activity of the p53 protein increases rapidly. As a result, the cell ceases to divide until the damage is repaired. In those cases where the damage is impossible to repair, the p53 protein instructs the cells to self-destruct so that the organism as a whole may live. In either case the p53 protein prevents the malignancy from evolving.
In normal cells, where the risk of malignancy is nonexistent, the ubiquitin system is responsible for the rapid breakdown of the p53 protein, preventing its accumulation in amounts that could disrupt the cell's normal operation. When the cell is "spoiled" in a way that may cause it to become cancerous, p53 is called into action and accumulates rapidly. The key to its accumulation is a disguise designed to help it evade the ubiquitin system. "Today we know that exposing cells to DNA damage causes the addition of phosphate molecules to the p53 molecule," says Oren. "These changes prevent identification of the protein by the ubiquitin system, and 'rescue' it." Oren and his team have recently begun to focus on defining the biochemical processes that oversee each of the phosphate sites and finding the mechanism by which phosphate affects the ability of the ubiquitin system to recognize the p53 protein.
They have discovered that a second protein, called Mdm2, is responsible for attaching ubiquitin, the "death tag," to the p53 protein. Thus Mdm2 is a critical factor involved in regulating the levels of the p53 protein in the cell. "According to recent information, some of it acquired in our lab, it seems that the rate at which p53 is broken down may be altered not only by changes caused by phosphates, but also by variations in the concentration and activity of Mdm2 in the cell," says Oren.
Red: Nucleii containing p53. Green: Nucleii genetically engineered to express Mdm2. In these cells, p53 does not accumulate because it is broken down by the ubiquitin system.
p53 fulfills a major role in the processes that affect the accretion, or nonaccretion, of genetic mutations that may lead to the development of cancer. "The cells have developed complicated warning systems, each of which can delay the breakdown of p53, thus preventing cancerous processes," says Oren. "If we can understand how the breakdown of p53 is modulated, we can intervene in this process using medication and boost mechanisms that protect from cancer."
As a result of Oren's research, drugs that cause increased p53 activity in cancerous cells by interfering with its breakdown via Mdm2 are being developed by several drug companies, in an attempt to arrest proliferation and even induce tumor remission.
From left to right: Prof. Eilam Gross, Prof. Giora Mikenberg and team member Meir Shoa
Once upon a time the universe was a simple place. It was composed of a few particles interacting by means of just one basic force. But being a very hot and extremely energetic universe, it existed for only a few seconds following the Big Bang. As the seconds passed, the energy spread out through the expanding space and the universe cooled, exactly like a cup of tea.
Its primary particles, able to exist only at very high energy levels, continued to multiply and form complex, highly charged relationships. In this way we progressed, more or less, from a simple primeval universe to our more complex cosmos, where we can recline and sip our tea (though it is cooling as well) while perusing at leisure articles on scientific principles.
For most of us, the complex place in which we live is a world filled with visual marvels. But physicists are not content with visible reality; their quest is to get to the root of its forces and to examine whether our visual reality is truly based on the profound-but-lost simplicity of the ancient universe.
An important milestone in their scientific research was the unification of electromagnetic and weak forces into a single, more ancient force, known as the electroweak force. The remaining missing link for proving the existence of the electroweak force is a force-carrying particle named the Higgs boson.
Weizmann Institute scientists at the Nella and Leon Benoziyo Center for High Energy Physics are participating in an international effort to find the Higgs, which is considered responsible for providing mass to all the particles in the universe. The research is being conducted in the largest particle accelerator in the world, known as LEP, at the European Laboratory for Particle Physics (CERN), near Geneva. This accelerator is located in a circular 16.7-mile (27-km) tunnel, excavated 110 yards (100 meters) below the earth's surface.
Weizmann scientists Dr. Daniel Lellouch, Dr. Lorne Levinson, Prof. Eilam Gross, and Prof. Ehud Duchovni, led by Prof. Giora Mikenberg of the Particle Physics Department, Director of the Benoziyo Center, are working in Europe within the framework of scientific cooperation agreements signed between Israel and CERN.
In the accelerator, particles moving in opposite directions create numerous collisions. A highly energized system develops in the vicinity of the collision, similar to the conditions that existed among particles during the first moment following the Big Bang. As a result, the particles of matter are converted into energy. This is an illustration of Einstein's famous equation; E=mc2 describes the equivalence between matter and energy. Subsequently, the energy spreads throughout the space and the system cools (just as happened in the developing universe). The energy is reconverted into particles of matter that undergo the same multistage process until they form the particles capable of existing in our familiar reality.
Scientists monitoring the various stages of this process are learning about the structure of matter and the development of the universe. But herein lies the rub: These energetic particles exist for only fractions of a second. To detect their very existence, it is necessary to identify the tracks they leave behind -- for which purpose scientists construct particle detectors. For example, in order to detect and identify the Higgs, the Institute's scientists, headed by Prof. Mikenberg, developed the thinnest gas-based particle detector in existence. This detector is capable of identifying tracks left by the passage of charged particles at a rate 50 times greater than that achieved by previous detectors. (Most of these detectors are made at the Weizmann Institute, while some are manufactured in Japan in close collaboration with Institute scientists.)
According to Mikenberg, unlocking the mystery of the Higgs depends primarily on its mass. "The heavier it is, the more powerful are the collisions required for its discovery. The current CERN accelerator is capable of producing collisions with an energy of about 200 billion electron volts."
What if the Higgs is too heavy for the current accelerator?
"In that event, the research will continue with a new accelerator now being installed in the circular tunnel, which will create about one billion collisions per second with energies that will, undoubtedly, trap this elusive particle."
The days of the Higgs as a particle-in-theory are numbered. If it ultimately transpires that the mass of the Higgs is close to 100 billion electron volts, it is likely that a supersymmetry will exist between the force-carrying particles and the "worldly" particles of matter.
It may also demonstrate the possibility that at the foundation of the material universe there existed a single, two-dimensional particle: a "superstring" -- the ancestor of all other particles.
The significance of this activity is the opening of a new and exciting hunting season for a swarm of anonymous particles filling key positions in the complex reality of our world. The real prize upon finding them could be the long-sought proof that at the origin of reality there existed a one-and-only basic force of nature, the descendants of which exist today.
Prof. Yoram Shechter (bottom left), Prof. Matityahu Fridkin (bottom right) and team members
The next item to join the miniaturization trend may soon be the medicine cabinet. Weizmann scientists have found a way to prolong the effect of medication; instead of taking a medicine tablet, say, four times a day, you'll only need to gulp it down once.
For example, the method, developed by Prof. Matityahu Fridkin of the Organic Chemistry Department, Prof. Yoram Shechter of the Biological Chemistry Department and Dr. Eytan Gershonov, who worked with both departments, has reduced the number of insulin injections needed in diabetic rats to a fourth. Instead of requiring two injections a day to keep glucose levels at a normal level, once in two days was sufficient.
Normally, when medication is taken, its level in the blood surges -- sometimes up to one hundred times more than what is needed for effective action. These high levels often produce damaging side effects, but are necessary to keep the drug in the bloodstream long enough to do its job. Then, within minutes to several hours, the drug is cleared from the circulation and a new dose is needed.
For several decades, scientists have been trying to invent a way of releasing drugs into the blood in a more even manner while prolonging the time the medication actively circulates in the body. However, this goal was achieved for only a very limited number of drugs.
Fridkin and Shechter's new technique may affect how numerous categories of drugs, including antibiotics and cancer medications, are released into the body. They devised several kinds of molecular "corks," each with a different tendency to disintegrate in the bloodstream, and attached them to the medicine's molecules. According to the scientists, the corks prevent the medicine's active ingredients from seeping into the bloodstream in large quantities. Corks more prone to disintegration come off first, releasing the active medicine ingredients, while those less prone to disintegration hold out longer. Thus, the corks release relatively low but steady quantities of the drug into the patient's bloodstream over a longer period of time.
The cork is a small organic molecule. In a test tube study, the Weizmann Institute scientists found that it slowly disconnects from the drug under the temperature and pH conditions equivalent to those in human blood.
By altering the molecule's chemical features, the scientists created different versions of the molecular cork that can be disconnected at different rates, so that the speed of the drug's release into the circulation can be more precisely controlled.
A cabinet full of drugs
Two additional aspects of this technology could contribute to the drug's long-term action. First, drugs modified with the cork are less susceptible to breakdown by enzymes than their unmodified counterparts. Second, the scientists have evidence that their cork attaches to a protein in the bloodstream that traps and holds onto it. This "hold" may prevent the drug from being cleared from the body too quickly.
Currently, the Institute scientists are exploring an additional potential advantage of this technology. Test-tube experiments suggest that the cork may improve drug absorption by the intestines. If these findings are supported by further animal studies, the cork may be used to help change the chemical properties of injected drugs so as to convert them into oral medications.
A start-up company, Lapid Pharmaceuticals Ltd., has recently been created by Pamot Venture Capital Fund and Yeda Research and Development Co. Ltd., the Weizmann Institute's technology transfer arm, in order to develop this technology for commercial use.
If all goes as planned, medication takers may have a reason to open a bottle of champagne. With a corkscrew, of course.
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 with his team (left to right)- Dr. Illia Ravinovich%2C Alexander Milov%2C Alex Cherlin%2C and Dr. Wei Xie.jpg)
 and Prof. Tsvee Lapidot (left).jpg)
%2C Prof. Matityahu Fridkin (bottom right) and team members.jpg)
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