Sensing the growing shadow, it slithered away from its enemy, propelling itself with rapid, snakelike arm movements. Sounds like yet another episode in nature's daily drama of survival, but there's a puzzling catch - this creature doesn't have eyes.
Cousin to the sea urchin, sea cucumber, and starfish, the brittlestar is a marine invertebrate with five thin arms emanating from a disc like body, and no specialized eyes. How these sightless animals are able to detect shadows and hence flee danger has baffled investigators for years.
Weizmann Institute scientists, together with researchers at Bell Laboratories in New Jersey and the Natural History Museum in Los Angeles, now have an answer. Focusing on brittlestars of the species Ophiocoma wendtii, Profs. Lia Addadi and Steve Weiner of the Institute's Structural Biology Department discovered that these animals form crystal lenses in their skeletons. Recently reported in Nature, this unique 'visual' system is the first of its kind to be discovered in animals inhabiting the Earth today.
Addadi and Weiner had long been interested in the ways in which animals build their skeletons. Their research revealed that animals can produce different types of proteins, some of which control crystal formation.
The idea for the current study was born when they met Dr. Gordon Hendler of the Natural History Museum of Los Angeles County. Hendler brought to their attention one particular species of brittlestar that appears to be especially sensitive to changes in light, quickly escaping into dark crevices at the first sign of danger. It also changes its color from dark brown during the day to gray at night. Hendler suspected that the arrays of spherical crystal structures on the surace of its outer skeleton serve as lenses, transmitting light to the brittlestar's nervous system. His hypothesis was strengthened by the finding that these creatures have relatively extensive nerve networks. Moreover, the movement of pigmented cells between the crystal structures and the nerves appeared to alter the brittlestar's response to light.
Addadi and Weiner, together with their then graduate student Joanna Aizenberg, began to study the phenomenon. They discovered that each skeletal lens is actually a single calcite crystal. The crystal's optic axis is roughly perpendicular to the plane of the lens array, making it capable of transmitting light without the light being split in different directions. By analyzing the geometry of the lens they were able to pinpoint the expected focal point on the nerve bundles below. But is this light information really passed on as expected? In other words, do the lenses indeed guide and focus the light to effectively transmit it to the nervous system within?
This question remained unanswered for almost ten years, until the scientists found a way to examine the lenses using lithography, a semiconductor technology. The study was conducted at Bell Laboratories.
Aizenberg removed a calcite crystal array from the skeletal element of the brittlestar species Ophiocoma wendtii, placed it above a layer of photosensitive material, and exposed the system to light. She found that light had reached the photosensitive tissue in spots directly underneath the calcite crystals. By altering the distance between the lenses and the tissue, she found that the estimated focal distance of each lens - at which the lens concentrated the light by a factor of about 50 - coincided with the depth at which nerve bundles, which presumably serve as photoreceptors, are located in the brittlestar's body.
Like the human eye, then, the crystalline lenses and the pigmented cells in the skeleton of Ophiocoma wendtii act as 'corrective glasses,' filtering and focusing light on the phtoreceptors. But unlike man's ability to see in virtually only one direction, this complex visual system enables the brittlestar to detect approaching danger from any direction. The lenses also focus light at least 10 times better than any micro-lense manufactured today. Indeed, the unique brittlestar architecture is already giving rise to new ideas in materials science, such as the use of tiny lenses for various applications, including computers and telecommunication.
This is the first discovery of this type of visual system in animals, although Weiner notes that calcite crystals were used in the compound eyes of trilobites, marine animals now extinct, that inhabited the earth some 350 million years ago.
'The demonstrated use of calcite by brittlestars, both as an optical element and as a mechanical support, illustrates the remarkable ability of organisms, through the process of evolution, to optimize one material for several functions. It may also spark new ideas for future 'smart' materials,' say the scientists.
Prof. Lia Addadi holds the Dorothy and Patrick Gorman Professorial Chair. Her research is supported by the Minerva Stiftung Gesellschaft fuer die Forschung m.b.H.
Prof. Stephen Weiner holds the Dr. Walter and Dr. Trude Borchardt Professorial Chair in Stuctural Biology. His research is supported by the Helen and Martin Kimmel Center for Archaeological Science; Mr. George Schwartzman of Sarasota, Florida; and the Angel Faivovich Foundation for Ecological Research.
Chop it up, unzip it, make numerous copies of it in less than an hour, or even edit it, slipping in a trait for, say, bacterial resistance or insulin production. Seems like there's no end to the stuff one can do nowadays to DNA. And future aims are no less extraordinary, like the attempt to harness DNA as wiring for microelectronics.
All this, however, calls for a greater understanding of the physical properties of DNA, including the way in which it 'unzips' itself when exposed to heat a process called denaturing.
The shape of the DNA molecule has been known since 1953 when American microbiologist James Watson, then only 25, and English physicist Francis Crick discovered its double helical structure, earning them the 1962 Noble Prize. (They shared the prize with Maurice Wilkins of Kings College, London, who had solved the problem independently at the same time.)
The key they discovered was chemistry. Shaped like a spiral staircase, the DNA molecule consists of two winding strands of alternating sugar and phosphate molecules. But the most interesting part of the molecule from a genetic perspective is not these strands but rather the way in which they are linked. Four nitrogen-containing bases: adenine, cytosine, guanine, and thymine (referred to as A, C, G, and T) wind up the helix, forming 'steps' as each base pairs up with a counterpart on the other strand. The sequence is far from random: A always pairs up with T, and C with G. Indeed, Watson and Crick realized that the strict chemical rules dictating the nature of these cross-links underlie the marvel of the DNA molecule. The specific sequence of A's, T's, C's, and G's along each DNA strand actually constitutes a code translated by cell machinery to synthesize proteins. Likewise due to these chemical rules, DNA is capable of duplicating itself with generally remarkable precision, unzipping the helix and using each strand as a template to direct the formation of a companion strand.
Later studies showed that the DNA molecule also 'unzips' itself (albeit with a drastically different outcome) when exposed to temperatures of about 70°C. During this separation process, loops form in certain parts of the genetic material but not in others. Why is this so? Scientists studying this physical phenomenon discovered that it stems from differences in the strength of the nucleotide bonds. The A-T bond is weaker than the C-G one. As a result, genetic sequences containing more A-T bonds will come apart faster and more easily than those rich in C-G bonds.
And this finding, made in the late fifties, years before advanced genetic sequencing methods were devised, stirred up a great deal of excitement. Scientists hoped to use statistical data on the location of these loops to backtrack to the DNA molecule itself, gaining information about its genetic sequence. This is where physicists studying different types of phase transitions became interested. The scientists, including the late Prof. Shneior Lifson of the Weizmann Institute, examined DNA models containing only A-T nucleotide bonds and showed that in these models, the transition from normal to 'loopy' DNA structure occurred gradually, with the loop size continuously increasing. However, experimental observations of loop formation in genetic material disproved this finding. The loops, they showed, did not increase in a slow and tidy fashion, since the DNA strands actually unzipped suddenly.
This frustrating contradiction in scientific knowledge persisted for more than 30 years, until graduate student Yariv Kafri of the Institute's Physics of Complex Systems Department, Prof. David Mukamel, Dean of the Physics Department, and visiting scientist Prof. Luca Peliti of the University of Napoli in Italy decided to take another look. They discovered that all the theoretical models used to describe the phenomenon contained a major flaw: they allowed adjacent DNA loops to overlap. Yet such overlapping never takes place in nature, since the DNA strands electrically repel each other.
This insight led the Institute scientists to study the possible ways in which DNA loops can arrange themselves in space while avoiding any overlapping between different loops and between the folded strands of the same loop. To describe the range of possible loop interactions, the researchers used mathematical knowledge gained from the study of various polymer networks. Once the avoidance of overlapping was taken into account with the help of these precise calculations, the modified theoretical models began to fit with experimental observations. The researchers predicted that when exposed to heat, transitions from a normal genetic sequence to loop formation happen suddenly just as in nature a phenomenon observed in laboratories around the world.
An accurate description of DNA may help in developing diverse applications, including a surprising partnership between microelectronics and natural molecules. The idea is to integrate organic molecules into microelectronics, to replace conventional components such as transistors, memory elements, and wires. This merger, say experts, may yield computer components thousands of times more compact than those presently available.
Prof. Mukamel holds the Harold J. and Marion F. Green Professorial Chair.
Glaucoma is the leading cause of blindness in adults, affecting one percent of the adult population. Weizmann Institute scientists have now succeeded in putting the brakes on progressive eyesight loss in experimental animals afflicted with a glaucoma-like disease. Their study, reported in Proceedings of the National Academy of Sciences, U.S.A., suggests that Copaxone, a drug developed at the Weizmann Institute to treat multiple sclerosis, may also stop, or at least slow down, eyesight loss in people with chronic glaucoma.
The majority of patients with chronic glaucoma have increased pressure inside the eye due to defective drainage of the transparent fluid that bathes the eye and nourishes its outer cells. This intraocular pressure (IOP) damages the optic nerve, causing it to degenerate and often leading to blindness. (Operating much like an electric cable, the optic nerve is a bundle of more than 1 million nerve fibers, which carry the images we see to the brain.)
For many years, the search for improved glaucoma therapies focused on correcting the eye's drainage system to reduce IOP. Eventually however, it became apparent that reducing the pressure was not enough to arrest glaucoma, as it did not halt optic nerve degeneration. Scientists concluded that a crucial factor was somehow being overlooked, and they set out in search of this missing link.
Approximately five years ago, Prof. Michal Schwartz of the Weizmann Institute's Neurobiology Department proposed a new concept to account for the continued optic nerve degeneration occurring in spite of successful treatments to reduce eye pressure. Schwartz suggested that while the initial damage to the optic nerve is indeed caused by increased eye pressure, secondary factors triggered by the initial damage contribute to the nerve's ongoing degeneration. When the nerve is damaged, chemicals that normally play an important role in neuronal cell maintenance increase to a toxic level. One of these chemicals is the neurotransmitter glutamate, which spills from damaged nerve cells and adversely affects healthy neighboring cells.
In line with this concept, Schwartz developed an original strategy for tackling the problem. To protect the nerve from the harmful chemicals in the body, she recruited the immune system (although its well-known role is actually to defend the body from external "invaders"). This approach raised eyebrows at first, mainly because it involved cells that, when activated, usually cause one of the autoimmune diseases, in which the body mistakenly attacks itself - such as juvenile diabetes and multiple sclerosis. The concept of using these "enemy" cells to heal the body seemed uncanny.
Schwartz - who has also developed an immune-based therapy for spinal cord injuries now undergoing clinical trials - has demonstrated that contrary to accepted wisdom, autoimmunity can play a beneficial role in the body. A series of studies in her lab showed that in rats, immunization with protein fragments from myelin, the sheath enveloping nerves, reduces the extent of degeneration after acute injury of the rat optic nerve or spinal cord. However, the clinical use of such protein fragments, or peptides, for immunization is fraught with risk because some of these peptides cause the immune system to attack nerve fibers, leading to multiple sclerosis. Since humans vary greatly in their genetic make-up, it is difficult to establish which of the peptides would be risky in a specific patient.
Looking for a safe alternative to these peptides to treat glaucoma, Schwartz and her group, in collaboration with Profs. Irun Cohen and Michael Sela of the Weizmann Institute's Immunology Department, turned to Copaxone, a synthetic compound which reacts with immune cells that recognize and respond to self proteins. Copaxone was developed at the Institute by Dr. Dvora Teitelbaum and Profs. Ruth Arnon and Michael Sela as a drug for multiple sclerosis. The team demonstrated that in glaucoma, immunization with Copaxone protects the damaged optic nerve from neuronal degeneration. And the most recent study by Schwartz, Dr. Eti Yoles, and graduate students Jonathan Kipnis and Hadas Schori may explain why. The Weizmann team found that immunization with Copaxone shields the nerve from the toxic effects of neurotransmitter glutamate. These studies were corroborated in another series of experiments, conducted together with scientists at the U.S. based company Allergan Inc. (who developed the rat model that simulates chronic glaucoma). In rats immunized with a single injection of Copaxone, only about 4 percent of the nerve cells in the glaucoma-affected eye died, compared with 28 percent in the control group. These collective findings strongly suggest that Copaxone immunization is a potential therapy for glaucoma. Following these findings, trials in human patients with glaucoma are expected to begin shortly. Scientists hope that the trials will be facilitated by the fact that the U.S. Food and Drug Administration has already approved the use of Copaxone.
Prof. Avraham Ben-Nun. Neutralizing autoimmune attacks
Autoimmune diseases can be likened to a sweeping forest fire in which the immune system attacks one of the body's proteins, mistaking it for an "enemy," and then proceeds to attack other proteins in the affected organ. This relatively recent insight into the "forest fire-like" development and progression of autoimmune diseases demonstrates the daunting challenge faced by researchers seeking to block their advance.
Why autoimmune diseases occur is still a mystery, but they appear to stem from the immune system's failure to distinguish between foreign, disease-causing agents and the body's own proteins. Juvenile diabetes, for instance, is caused when a protein essential for the proper functioning of insulin-producing cells is mistakenly attacked, while multiple sclerosis develops when the immune system erroneously attacks the myelin sheath around nerve fibers in the central nervous system.
One approach in the struggle against autoimmune diseases has been to weaken the entire immune system. However, this leaves the body extremely vulnerable, which is why scientists are anxious to find means to selectively target the immune system's faulty attacks against the body's proteins without affecting its ability to combat foreign invaders. To this end, Prof. Avraham Ben-Nun of the Weizmann Institute's Immunology Department has developed a new strategy for treating autoimmune diseases, particularly multiple sclerosis.
For years, scientists studying multiple sclerosis assumed that the immune system's attack on myelin focused on one of myelin's most abundant proteins, called myelin basic protein, or MBP. Further studies, showed, however, that the attack can also be directed against another myelin protein, called proteolipid protein, or PLP. And the list continued to grow. Several years ago, Ben-Nun and Dr. Nicole Kerlero de Rosbo showed that a third protein, myelin oligodendrocyte glycoprotein, or MOG, is also targeted; and recently Ben-Nun and his colleagues discovered two additional myelin proteins that draw the immune system's "fire" in multiple sclerosis.
These findings drove home the complexity of uncovering autoimmune disease processes. Further studies revealed that not only can a mistaken immune attack against any of these five proteins trigger multiple sclerosis, but the major proteins targeted can vary from patient to patient, and in a given patient at different stages of the disease. Just like a forest fire, the immune attack may initially target one protein but then spread to any or several of the other five proteins, sequentially or simultaneously, while often abandoning the original target.
It became clear that to selectively suppress harmful autoimmune responses without shutting down the entire immune system one would have to identify the specific proteins targeted in each patient at any given stage - a process requiring complex, expensive, and time-consuming tests. Ben-Nun set out to devise a therapy theoretically suitable for most patients - one that would selectively neutralize an autoimmune attack against any of the five proteins, regardless of which protein is attacked. For this purpose his team identified the main "draw-fire" regions on each of the five target proteins, using biological testing methods and computer modeling in collaboration with Dr. Miriam Eisenstein of the Weizmann Institute's Chemical Services Unit. Then, using genetic engineering, Ben-Nun with the assistance of Dr. Lydia Cohen, generated a synthetic gene in which all of these regions are encoded in a sequential molecular chain. This synthetic gene was subsequently introduced into bacteria, which then produced the novel "draw-fire regions" protein - a protein that does not exist in nature.
When administered under certain conditions, this genetically engineered protein was found to protect mice against multiple sclerosis-like disease whereas injection under other conditions led to disease onset. Ben-Nun and his colleagues also demonstrated that it is possible to vaccinate mice against the disease using the gene itself. When incorporated into mouse cells, this gene serves as a "data bank," allowing the cells to manufacture the "draw-fire regions" protein, thus eliminating the need for continuous protein administration. This strategy was employed by the Institute scientists to design synthetic genes coding for "draw-fire regions" proteins pertinent to immune-specific therapies for several autoimmune diseases: a protein called Y-MSP for potential treatment of multiple sclerosis, Y-DMP for juvenile diabetes, and Y-RAP for rheumatoid arthritis. Yeda Research & Development Co. has filed a patent application for this approach.
In current studies Ben-Nun and his colleagues are further developing their approach to produce genetically engineered "draw-fire regions" proteins modified to effectively suppress these autoimmune diseases without triggering other disease processes.
Other scientists participating in this study were Dr. Gregor Sappler and research students Itzhack Mendel, Ming-Chao Zhong, and Joel Kay, all of the Weizmann Institute's Immunology Department; Dr. Roni Milo, Neurology, Assaf Harofeh Medical Center; Prof. Oded Abramsky, Neurology, Hadassah University Hospital; and Dr. Michael Hoffman and Prof. Israel Yust, Internal Medicine, Ichilov Medical Center.
Prof. Shimon Reich. Discovering superconductivity in a "backyard" materials science substance
Old horses, like old dogs, may be unable to learn new tricks, but a substance described as the "old workhorse" of the materials sciences, a material used for years to study the conduction of electric currents, has just revealed a startling new property. Weizmann Institute scientists have shown that this material transforms into a superconductor at a relatively high temperature.
Superconductivity is an intriguing phenomenon in which a material cooled to a certain temperature suddenly loses all resistance to electric current, allowing the current to flow indefinitely. When first identified in 1911, superconductivity was thought to be present in metals cooled to several degrees above absolute zero (-273°C) and later in alloys at temperatures not exceeding 25 degrees above absolute zero. But a new era began in 1986, when cuprates - ceramic materials in which copper and oxygen are arranged in a layered structure - were found to become superconductors at much higher temperatures, up to 133 degrees above absolute zero. The discovery made superconductivity vastly more accessible both for research and for potential applications. Cooling an object to these (relatively high) temperatures is comparatively simple and cheap - it can be done with the help of liquid nitrogen, which is much less expensive than the liquid helium required for the classic superconductors. High-temperature superconductivity is now a major branch of physics and materials science, involving thousands of researchers worldwide and promising to lead to numerous practical applications, from superconducting transmission lines to improved MRI machines.
Until now, high-temperature superconductivity was known to exist only in cuprates, but Weizmann Insitute scientists have for the first time demonstrated the phenomenon in an entirely different material. Prof. Shimon Reich and graduate student Yitzhak Tsabba of the Materials and Interfaces Department made this discovery while studying the magnetic properties of tungsten trioxide containing traces of sodium. The scientists were surprised to find that the material showed signs of superconductivity at 91 degrees above absolute zero, or -182°C (-296°F). In a follow-up study conducted in collaboration with Institute colleague Dr. Gregory Leitus and Dr. Oded Millo of the Hebrew University of Jerusalem, the researchers revealed that super-conductivity was not induced throughout the bulk of the material but only at its surface, in tiny microscopic "islands" measuring millionths of a millimeter. Some of these results were corroborated in an electron spin resonance study performed by Nobel laureate Prof. Alex Mueller and Dr. Alexander Shengelaya, both of the University of Zurich, in collaboration with the Weizmann scientists.
superconductive surface
In the wake of the Weizmann Institute discovery, Physics World, a popular physics magazine, recently posed the question as to whether high-temperature superconductivity would now result in a shift from the "copper age" to the "bronze age." This tongue-in-cheek comment referred to the fact that cuprates contain copper, while the material used in Reich's study, with its sodium content increased, belongs to the class of so-called tungsten bronzes - metallic compounds widely used as paint pigments because of their ability to produce a striking range of colors. Whether or not the shift occurs, the discovery of an alternative to ceramic cuprates opens exciting new research possibilities in the area of high-temperature superconductivity.
Dr. Yinon Rudich: Dust storms "dampen" rain prospects
The incurable nomad, dust travels enormous distances. Originating primarily in deserts, dust from Africa may end up in Florida, while dust from China can be found in California. Dust particles floating in the air absorb incoming solar radiation as well as radiation emitted by Earth's surface. In this sense, their environmental impact is similar to that of greenhouse gases. The temperature on Earth rises when the ground absorbs visible solar radiation and, in turn, radiates heat. This radiation is partly absorbed by atmospheric greenhouse gases, such as water vapor, carbon dioxide, and ozone and consequently does not dissipate into outer space. Known as the "greenhouse effect," this process occurs naturally and is essential for the existence of life on Earth.
In contrast, however, to the absorption of heat radiated from the ground by greenhouse gases, dust particles also absorb and disperse incoming solar radiation, so that their climatic impact is more complex. The chemical composition of dust particles affects various biological systems and environmental processes. For example, when dust particles contain iron, they absorb more solar radiation. Iron-rich dust particles are also an important nutrient for plankton. (Greek for "drifters," these microscopic oceanic organisms form the base of the aquatic food chain and are estimated to account for much of the atmospheric oxygen produced.) However, when these dust particles reach densely populated areas, the dust-borne iron can become a health hazard, causing the formation of free radicals that attack lung tissue.
Seeking to better understand how the chemical composition of dust particle affects atmospheric and environmental processes, Dr. Yinon Rudich and graduate student Alla Falkovich of the Weizmann Institute's Environmental Sciences and Energy Research Department have conducted a series of studies using a novel approach. They focused on the impact of atmospheric aerosols and dust particles on clouds - one of today's greatest challenges in piecing together the factors affecting the climate on Earth.
Using an electron microscope and a system they developed based on mass spectroscopy, the research team set out with several ends in mind: to identify and analyze the chemical properties of dust particles originating in the Sahara desert, to characterize the organic materials attached to these dust particles, and to determine where a particular element is mainly concentrated - on the particle's surface or at its center. Studying particles collected during a severe dust storm in Israel in March 1998, the scientists found that these particles are covered with iron and sulphur (sulphur is usually found in acids and salts that dissolve in water). In these samples, the lack of sea salt particles and sulfate aerosols (which commonly influence cloud properties) led to the conclusion that the sulphur coating the dust particles had originated from the soil of the source region. In other words, the sulphur arrived in the atmosphere via a natural dust storm and not because of an interaction between dust particles and polluted air, as had been earlier believed.
The presence of a soluble material on the surface of particles is key to understanding the effect of dust on clouds. To probe this effect, the scientists collaborated with Prof. Daniel Rosenfeld of the Hebrew University of Jerusalem to analyze data from the same cloud and rain system obtained through research satellites and aircraft. By combining these data with the results of the chemical analysis, they found that clouds formed in a dust-rich area did not produce rain, whereas clouds outside the area influenced by dust did. Simply put, dust storms inhibit rain formation.
Unpolluted Versus Dust- Rich - Atmosphere
The researchers concluded that the coated dust particles serve as cloud-condensation nuclei around which water drops form. The presence of many cloud-condensation nuclei in the air leads to the formation of clouds with a large number of small drops of water. In such clouds, the coalescence of drops - essential for an increase in droplet size and the production of rain - is blocked. Thus a high concentration of atmospheric dust reduces rainfall; this in turn leads to parched soils, which then cause the formation of more dust, and so on. This feedback mechanism between dust and rainfall may explain the desertification process taking place in the Sahel (a region of Africa, south of the Sahara, from Senegal eastward to Sudan. In this respect, it resembles the effect of forest fires raging in Indonesia and in the Amazon basin on rainfall in these areas. The fires release into the atmosphere large quantities of aerosols, whose solid or liquid components function as cloud-condensation nuclei, reducing rainfall.
According to Rudich, the link between dust particles and cloud properties affects climatic phenomena in many additional ways. In the coming years, such links and their interpretation will be at the center of studies conducted by researchers at the Weizmann Institute and at other institutions in Israel and around the world.
Prof. Abraham Amsterdam: Fine-tuning reproductive levers
Sounding in part the shrewd financial investor, in part the philosopher, Prof. Abraham Amsterdam is fascinated by windows of opportunity - from an ovary's perspective, that is.
As more and more women pursue successful careers, many are waiting well into their 30s and some into their 40s to have children. Much of the freedom to do so stems from a profound change in life expectancy rates. In 1880, a woman's average life span was only 45. Today, a Western woman has a fair chance of raising a toast on her 80th birthday and beyond.
New times, new customs. Yet one thing hasn't changed - a woman's biological clock. While a healthy 35-year-old woman is just as likely as a 25-year-old to deliver a normal, healthy baby, her chances of becoming pregnant within the first year of "trying" are roughly 50 percent. This rate plunges to 27 percent for women aged 40 to 44, accompanied by a one-in-three chance of miscarriage.
What controls this biological clock? And how can science be used to curb its relentless beat?
Prof. Abraham Amsterdam of the Weizmann Institute's Molecular Cell Biology Department is probing the cellular cross-talk determining ovarian function. A better understanding of this ticking puzzle might reduce the age-related decline in female fertility and may also yield important fringe benefits, delaying the dramatic increase in ovarian cancer, cardiovascular disease, and osteoporosis that mark the onset of menopause.
"Ovarian cell death is actually an essential process," Amsterdam emphasizes. The mammalian cycle is characterized by a Darwinian race between follicle-enclosed ova. One of the follicles (the dominant follicle) eventually takes the lead and excretes compounds suppressing the development of the other follicles. In spite of a woman having roughly 500,000 eggs before puberty, on average only 480 of these will reach ovulation.
Why must so many eggs be eliminated? "One can describe this as a 'death-for-life' phenomenon," says Amsterdam. "It's essential to eliminate the extra eggs; otherwise the human race would cease to exist, since women cannot normally have multiple-embryo pregnancies."
Interestingly, the process governing ovarian cell death is the same as that which plays a central role in protecting the body against cancer. Known as apoptosis, or programmed cell suicide, it is how the body rids itself of surplus or damaged cells. "Our primary goal is to learn how to fine-tune ovarian cell death," says Amsterdam. "The ability to induce apoptosis may lead to future treatments for ovarian cancer. On the other hand, by suppressing apoptosis we may extend a woman's reproductive years."
Motherhood as a Marionette
Achieving this goal - as Amsterdam and others are increasingly discovering - is all about determining ways to maneuver the intricate cross-talk between genes and their protein products. The key is to learn which levers to push - and how. It's much like operating a marionette. The strings of the marionette include hormones, apoptosis-inducing "death genes," and their alter ego, "survival genes." The first steps in this direction have already been taken. Working with doctoral student Ravid Sasson and Dr. Kimihisa Tajima, a visiting physician from Japan, Amsterdam has recently discovered that glucocorticoids (hormones such as cortisol and cortisone) protect ovarian cells from apoptosis. As reported in Endocrinology, the study demonstrated that glucocorticoids have a dual effect. "While they protect ovarian cells from apoptosis, they have the opposite effect on white blood cells taking part in the inflammatory process during menstruation," says Amsterdam.
Like glucocorticoids, Leptin, secreted by adipocytes (fat cells), dramatically reduces ovarian cell death, as well as controlling sex hormone production. Working with doctoral student Dalit Barkan and Prof. Menachem Rubinstein of the Institute's Molecular Genetics Department, Amsterdam found that both leptin and the glucocorticoids exert their effect through a central behind-the-scenes mediator: the Bcl-2 survival gene. He is currently collaborating with physicians at Rehovot's Kaplan Hospital and the Tel Aviv and Sheba Medical Centers to examine the effect of these substances on women undergoing in vitro fertilization.
What about a broader, standard treatment for young women wishing to push the "snooze button" on their biological clocks while they pursue advanced degrees, start a company or travel around the world? "Currently, this remains a distant prospect," says Amsterdam. "Nevertheless, a better understanding of apoptosis in normal ovarian function may yield other benefits, including improved treatments for ovarian pathologies. Recent evidence links impaired apoptosis with polycystic ovaries (which cause infertility) as well as with ovarian cancer - the number one gynecological killer."
Anti- Inflammatory action of Glucocorticoids in the Ovary
Like glucocorticoids, Leptin, secreted by adipocytes (fat cells), dramatically reduces ovarian cell death, as well as controlling sex hormone production. Working with doctoral student Dalit Barkan and Prof. Menachem Rubinstein of the Institute's Molecular Genetics Department, Amsterdam found that both leptin and the glucocorticoids exert their effect though a central behind-the-scenes mediator: the Bcl-2 survival gene. He is currently collaborating with physicians at Rehovot's Kaplan Hospital and the Tel Aviv and Sheba Medical Centers to examine the effect of these substances on women undergoing in vitro fertilization.
What about a broader, standard treatment for young women wishing to push the "snooze button" on their biological clocks while they pursue advanced degrees, start a company, or travel around the world? "Currently, this remains a distant prospect," says Amsterdam. "Nevertheless, a better understanding of apoptosis in normal ovarian function may yield other benefits, including improved treatments for ovarian pathologies. Recent evidence links impaired apoptosis with polycystic ovaries (which cause infertility) as well as with ovarian cancer - the number one gynecological killer.
In almost every movie plot you'll find "good guys" and "bad guys." In our bodies, cancer-related genes can be similarly divided into two such groups - cancer suppressors and cancer promoters. A few years ago Prof. Adi Kimchi of the Weizmann Institute's Molecular Genetics Department uncovered a group of suicide genes that may suppress cancer. In a paper published recently in Nature Cell Biology with graduate student Tal Raveh, she showed that one of these genes - DAP-kinase - plays an important role in a critical cancer-protecting "junction."
Various tumor suppressor genes, including the group of genes discovered by Kimchi, operate by activating a genetic "suicide program" embedded in every cell in the body. When this program is activated, a living cell commits suicide. This phenomenon of self-destruction is called apoptosis - Greek for the falling of leaves. Impaired apoptosis leads to uncontrolled cell proliferation, which can result in tumor formation.
Knockout Genes
Kimchi and her team focused on the biochemical communications network governing apoptosis. In their attempts to identify "hidden" genes that carry out important functions in this network, they developed a new approach, which enables, for the first time, efficient "gene hunting" in mammalian cells. Their method, called TKO (technical knockout) is based on a series of processes involving genetic engineering that randomly disable various genes in cells. When a gene belonging to the "suicide program" network is disabled, that cell, which normally would have committed suicide, is "saved." By observing how "shutting down" a particular gene affects its cell, one can draw conclusions about this gene's role and identity. In this manner scientists can isolate a single gene out of 30,000.
In the past few years, Kimchi and her team have successfully used this method to discover five genes, called DAP (death associated proteins), that are connected to the death-inducing processes in cells. Their development of the TKO method and identification of the DAP genes have received international recognition and won Kimchi several awards, including the prestigious Milstein Prize.
Cancer-Blocking Gene
Recently, the scientists showed that DAP-kinase is responsible for destroying cells that have begun converting into a cancerous state. This is in fact a mechanism for "purging" tissues of cells containing early-stage cancerous abnormalities, such as certain oncogenes (cancer-causing genes). It turns out that the DAP-kinase mode of action includes activating another well-known tumor suppressor gene, p53, along with activating additional factors connected to the cell skeleton. In other words, DAP-kinase is the "trigger" that activates the p53 gene and leads to the destruction of oncogene-containing cells.
A malfunction of DAP-kinase disrupts the suicide program, allowing a cancerous growth to develop. The study's results are supported by the recent detection of DAP-kinase abnormalities in patients with cancers of the lung, breast, head, and neck, as well as in type B cell lymphoma. By improving the mapping of the biochemical "suicide command" chain in cells, the team's findings may aid the development of new cancer drugs.
Prof. Jeffrey Gerst (left) and Michael Marash: Cells have a "master switch" regulating secretion
Let's talk about secretion. This suggestion would probably cause more than a few raised eyebrows - especially if offered by the media. But science writing has its fair share of unusual tasks, which mirror the incredible diversity of scientific research. Take for instance the efforts to better understand secretion processes in yeast, the current research focus of Prof. Jeffrey Gerst and doctoral student Michael Marash of the Weizmann Institute's Molecular Genetics Department.
As it turns out, the study of yeast and other less-developed organisms holds the key to a better understanding of human cell secretion. In fact, the obvious differences between yeast, flies, and people dwindle unexpectedly when their mechanisms of secretion are closely observed.
Secretion, one of the most fundamental mechanisms of life, plays a central role in communication among living cells and is also involved in their construction and growth. Because the genes controlling this mechanism are well conserved in evolution, variations among species are relatively slight.
Gerst studies the genetic factors responsible for the cellular secretion of such substances as hormones and neurotransmitters. The secretion process begins with the formation, inside the cell, of a bubble containing the substance to be secreted. This bubble, or "vesicle," consists of a membrane of fatty molecules called phospholipids (the same molecules as those forming the cell membrane). When the secretion process is set in motion, it causes the vesicle to fuse with the cell membrane, resulting in the vesicle's contents spilling into the intercellular space (the space between cells). Vesicle-cell fusion is also an essential stage of cell growth: when the vesicle fuses with the membrane, the cell's surface grows, just as a quilt would expand if new patches were incorporated into its fabric.
How exactly does fusion between the vesicle and the cell membrane take place? Gerst, together with two other groups, found that this process is regulated by three proteins: Snc, Sso, and Sec9. Apparently, Sso and Sec9 are "irreplaceable" - when damaged, the secretion process is arrested and the cell dies. But more recently, Gerst has revealed that the third protein, Snc, has a "backup system." When this protein is damaged, genetic mutations in two other proteins (Vbm 1 and 2) may occur to restore cell growth and secretion. These mutations also have an interesting side effect - they lead to the cell's accumulation of precursors, called ceramides, required to build certain lipids.
The research team has now simulated this backup mechanism, leading to an important discovery - a "master switch" regulating secretion. When the scientists added ceramide precursors directly to the cells, the secreting cells continued to live and secrete properly even though one of the fusion factors was missing. The introduced material is, in effect, a sort of a chemical trigger that activates an enzyme, called a phosphatase, which breaks off a phosphorus-containing group of molecules from various proteins. The scientists established that this trigger operates not only in the backup system but also in Sso, one of the two "irreplaceable" fusion proteins.
Thus by identifying the "backup system" of one of the fusion proteins, Gerst and his team discovered the master switch. When one of the "irreplaceable" fusion proteins contains phosphorus, secretion is prevented; but when the phosphatase enzyme is activated and removes the phosphorus, the protein initiates membrane fusion, which in turn leads to secretion. The newly discovered role of this phospatase in secretion also shed s light on the enzyme's vital function in the growth of living cells.
A better understanding of these processes may lead to future ways of controlling the secretion process of various cells. For example, it may be possible to regulate the secretion of neurotransmitters by nerve cells, which could help treat degenerative brain diseases, or to control the secretion of hormones and other signaling chemicals, resulting in advanced cancer-treatments.
Step by step documentation of "midwife"-assisted amoeba reproduction
Giving birth has never been easy. Nature seems to have decided that whoever wants to procreate should make an effort. Sometimes the process of birth, the physical separation from offspring, is so difficult that a mother needs a helping hand. And humans are not alone in this trait, as recently reported in Nature. An interdisciplinary research team at the Weizmann Institute has discovered that "midwives" also play a role in the microscopic world of amoebas. It is this collaborative birth process that has given amoebas an evolutionary edge.
Amoebas are single-celled organisms that reproduce asexually. Reproduction occurs when an amoeba doubles its genetic material, creates two nuclei, and starts to change in shape, forming a narrow "waist" at its middle. This process usually continues until the final separation into two cells. However, Weizmann Institute scientists found that in one type of amoeba this separation process stalls just before its completion. The two cells remain connected by a narrow tether, which they have difficulty severing using the normal cleavage mechanism. Until recently scientists envisioned only two possible scenarios at this fateful stage. In the first, the two cells, the "mother" and the "daughter," tug at their connecting tether, stretching it until it breaks and each can start a life of its own. In the second scenario, the two tug at the tether but fail to disconnect. After a while they give up and revert to being a single cell, which now has two nuclei.
A collaborative study by physicists and biologists at the Weizmann Institute has now revealed a third scenario, involving a "midwife" amoeba.
Prof. Elisha Moses of the Physics of Complex Systems Department had been studying the mechanical and physical aspects of how living cells separate. He discussed his work with Prof. David Mirelman, Dean of the Biochemistry Faculty, who, among other projects, investigates the properties of amoebas. Mirelman suggested that they examine how amoebas - which multiply faster than most other eukaryotic cells - separate.
The study took place in Moses' lab, which is equipped with sophisticated systems for observing and documenting the physical processes taking place at the level of a single cell. Much to their surprise the team found that in a significant number of cases, when the two amoebas have trouble disconnecting, a third amoeba rushes to their aid. This amoeba squeezes between them, exerting pressure until the "umbilical cord" snaps and each amoeba is free to go its own way.
The research team, which included graduate students David Biron, Pazit Libros, and Dror Sagi, went on to show that the struggling amoebas send out a chemical cry for help. When amoebas are placed in a culture flask and fluid is collected near the narrow "waist" of a dividing amoeba and subsequently released elsewhere in the flask, it causes other amoebas to flock to that spot - just like midwives responding to a call from a woman in labor. The phenomenon was even more pronounced when the scientists merely moved the tip of the pipette containing the attracting substance around in the flask, causing the amoebas to "chase" it.
The scientists believe that the chemical signal released by a dividing amoeba is a unique complex substance present in the amoeba's membrane, consisting of a lipid, a protein fragment, and some sugars. When an amoeba is trying to divide, the membrane in the area of its narrow "waist" stretches, undergoing enormous stress. This mechanical perturbation may cause the substance to be released into the nearby environment, thus "alerting" the "midwife" amoebas to come to the aid of the dividing amoeba.
The researchers plan to further investigate this phenomenon, in particular the precise composition of the attractant, its mechanism of release by amoebas undergoing division, and the nature of the "midwife's" receptor. This study may contribute to future attempts to control amoeba-borne infectious diseases, such as dysentery, through new therapies targeting amoeba reproduction.
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 and Michael Marash- Cells have a master switch regulating secretion.jpg)
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