How smart were the hominids who inhabited our planet 1.5 millions years ago? Did the Phoenicians destroy the Mediterranean port of Dor? Until recently, you wouldn’t have expected Weizmann Institute research to throw light on such questions, but today’s Institute scientists are involved in a number of archaeological studies, including several conducted in an unlikely venue - a physics lab.

Prehistoric axes and pieces of ancient pottery began to appear in Weizmann’s physics building about three years ago, after Prof. Uzy Smilansky celebrated his 60^th birthday by taking his family to work at an archaeological dig in Ein Gedi. Smilansky, of the Physics of Complex Systems Department, had been fascinated by archaeology ever since he volunteered at the excavation of Massada in the 1960s during his army service. Returning to this lifelong interest, he set out to develop an objective, computerized method for analyzing large amounts of archaeological data.

One area of archaeology where computers might prove invaluable is the study of pottery - which provides a wealth of information about past civilizations, helping to date excavated layers, reveal social customs and trace trade relations. Sorting and classifying pottery finds is, however, an overwhelming task. Excavations generally churn up thousands of pieces of broken clay pots. Moreover, the use of artists to hand-draw the pottery shards potentially introduces a bias. Smilansky attacked these problems together with two archaeologists, Drs. Ayelet Gilboa of the University of Haifa and Ilan Sharon of the Hebrew University of Jerusalem, and graduate student Avshalom Karasik, who has a joint bachelor’s degree in archaeology and mathematics.

To produce objective digital images of pottery pieces, the scientists used a profilograph, a device that traces the outline of an object and transmits it to a computer. Next, they analyzed the resulting images using a mathematical algorithm that sorts the objects according to their curvature.

Initial results have proven promising. One of the studies examined findings from Dor - today a popular beach north of Tel Aviv, but in the distant past a bustling Mediterranean port and commercial hub.

Dor was excavated for two decades under the direction of Hebrew University’s Prof. Ephraim Stern and is now being explored under the guidance of Gilboa and Sharon. The digging had revealed layers belonging to the 12^th and 11^th centuries BCE, separated by a thick layer of debris.

Archaeologists assumed that the debris signaled a sweeping change in population: The Phoenicians, who conquered Dor from the Sea People in the 11^th century BCE, had apparently wrought widespread destruction. However, a computer analysis revealed that the pottery had undergone a continuous evolutionary change during the 12^th and 11^th centuries BCE, thus putting into question the effect of the Phoenician conquest on the local population. “Obviously, you can’t draw sweeping conclusions from this finding, but it does support the notion of cultural continuity. At the very least, the art of pottery continued to be passed on from father to son,” says Gilboa.

Another study offers a look into the brain power of our prehistoric ancestors by examining early Stone Age handaxes, found in abundance in Israel. The ones studied by the scientists were apparently left behind about 1.5 million years ago by Homo erectus migrating from Africa to Asia and Europe.

Smilansky, Karasik and Sharon, working with postdoctoral fellow and prehistorian Dr. Idit Saragusti, found that at three of the sites studied, the axes showed enhanced symmetry and smoothness over time - a finding that suggests the evolution of cognitive skills, since the ability to generate symmetry requires a certain degree of sophistication.

Since word of the new method got out, Smilansky has been approached by archaeologists in Israel and abroad and is currently involved in half a dozen collaborative projects. If the method’s popularity continues to grow, archaeological exhibits are likely to become a routine fixture in the Institute’s physics building.

This research was supported by a Bikura Grant from the Israel Science Foundation and by the Helen and Martin Kimmel Center for Archaeological Sciences at the Weizmann Institute. Prof. Smilansky’s research is supported by the J & R Center for Scientific Research and the Minerva Center for Nonlinear Physics of Complex Systems. He is the incumbent of the Professor Wolfgang Gentner Professorial Chair of Nuclear Physics.

The life stories of blood stem cells, rich in suspense and danger, could fill volumes. A new study at the Weizmann Institute of Science has come out with a dynamic model that, for the first time, captures these stories on film.

Every 15 minutes a stem cell travels from the bone marrow to the thymus gland, where it undergoes a grueling training period. Only a few survive. The training proceeds through several stations, each of which equips the cadet with the skills necessary for the next stage. The process is very risky: If the cadet goes to the wrong station it will die. If it goes to the right station yet performs incorrectly or receives too strong a stimulus it again will die. Those that survive – only 3% – become mature T cells, the top combatants of the immune system. What is the secret of their survival? Is it possible to forecast the survival chances of each cell? The factors determining life and death are many: a small change in the number of certain receptors on the cell, the level of expressed proteins, etc. Since the number of receptors and cells is very large, and the number of combinations they may form is even larger, the whole system is extremely complex. Until now, scientists have lacked the ability to obtain an integrated picture of this process without introducing gross over simplifications.

To overcome this problem, Prof. Irun Cohen of the Weizmann Institute’s Immunology Department collaborated with Prof. David Harel, Dean of the Mathematics and Computer Science Faculty. With their joint graduate student Sol Efroni they were able to build a dynamic model that describes the training process through animation. In other words, they took the script – an enormous amount of information accumulated through previous studies – and turned it into a moving picture of the working thymus. What’s more, it’s an interactive film, in which the scientists can change parts of the plot to see how varying circumstances affect the outcome.

Their approach, termed Reactive Animation (RA) was designed using Statecharts, a method developed by Harel around 20 years ago to facilitate the management of complex computerized systems (see box).

In watching the animated drama, the scientists were able to piece together how different circumstances (such as changes in the stem cell population due to cell death or birth) affect the training results. They were surprised to discover several previously unsuspected phenomena. It turns out, for example, that during training the thymus cells compete with one another in Darwinian fashion, and even interfere with one another’s performance.

To examine the importance of this competition, the scientists used the dynamic RA model to decrease the level of competitiveness among the cells. The result: The structure of the thymus gland became distorted and its normal function ceased. In other words, the competition among the cells is a critical phenomenon without which T-cell training cannot take place.

To assess the reliability of their program, the scientists designed an experiment in which they entered  the data characterizing the starting point of the thymus cell-training program. They then ran the program without interruption (i.e. without introducing new circumstances) to see whether the outcome would correspond to the training results occurring naturally in the body. The result was a direct match. 

The model’s ability to describe the behavior of this highly complex biological system will enable experimental biologists to examine theories relating to immune function, choosing those that best conform to reality. “A better understanding of the factors controlling the T-cell training process could one day be used to promote desirable immune responses, such as blocking autoimmune diseases and reducing the body’s rejection of transplants,” says Cohen.

RA could also prove helpful to the study of embryogenesis – a leading field in biology dedicated to exploring the remarkable process by which a single fertilized egg develops into a complex three-dimensional organism. One of the team’s findings was that it is possible to generate a detailed model of the thymus gland – its form and function – merely by providing the computer program with information about the gland’s cells, the way these cells interact, and the chemicals they secret. Future studies might apply RA in this fashion to study the development of other glands or even organs. The idea, says Cohen, would be to use RA to examine how the body’s components “speak” to and influence one another to orchestrate the development of the lungs, heart and other organs – all striking in their architectural waltz of form and function.

Statecharts

Statecharts provides a visual description of the behavior of big, reactive systems such as those present in airplanes, automobiles and phone networks. Recently, it has been used to describe biological systems. The method presents all known possibilities and the relations between them in systematic, hierarchical diagrams. A software tool called Rhapsody, devised by Prof. Harel with a company called I-Logix, implements and supports Statecharts.

In RA, the diagrams produced using Statecharts were programmed to interface in a novel way with Flash animation. 

Prof. Cohen’s research is supported by the Robert Koch Minerva Center for Research in Autoimmune Disease; Mr. and Mrs. Samuel Theodore Cohen, Chicago, IL; and the Minna James Heineman Stiftung. He is the incumbent of the Helen and Morris Mauerberger Professorial Chair in Immunology.

Weizmann Institute scientists have uncovered a key mechanism leading to the spread of cancerous colon cells and have succeeded in reversing their metastasis in laboratory tests. The study, published in the Journal of Cell Biology, raises hopes that target-specific drugs might be devised to prevent, or reverse, the metastatic stage of colon cancer.

The second most prevalent type of cancer in men and the third in women in the Western world, colon cancer is lethal largely because its cells spread to a variety of other tissues, primarily the liver.

Normal cell growth and repair are orchestrated through an intricate checks-and-balances system controlled by a circuitry of genes and their respective proteins. Tumor formation is generally triggered by a mutation in one or several of these genes, causing the circuitry to go off track.

The team of Institute researchers headed by Prof. Avri Ben-Ze’ev of the Molecular Cell Biology Department has now traced one of the key cellular circuitries that, when mutated, leads to metastatic cancer of the colon. Its main players are two “cell-gluing” molecules known as beta-catenin and E-cadherin, and a cancer-causing gene called Slug. The team showed that the malfunction of these adhesion-related molecules causes the cancer cells to break loose from the tissue and migrate to form another tumor at a distant site.

They found that abnormally high levels of beta-catenin (due to a mutation in the beta-catenin gene itself or in one of the genes controlling its breakdown) cause a surge in Slug, which then inhibits the production of beta-catenin's partner in cell adhesion, E-cadherin. The resulting E-cadherin shortage prevents the cell from adhering to adjacent cells. “The cell takes on a boat-like shape and, leaving the pack, enters the bloodstream and migrates to distant colon tissue, where it proceeds to multiply, forming a new tumor,” explains Ben-Ze’ev.

Drug for Slug

The scientists found that when colon cancer cells are surrounded by other such cells in the crowded environment created in a test tube, minute quantities of E-cadherin recruit beta-catenin from the nucleus and bind to it. Lower levels of beta-catenin in the nucleus then result in decreased Slug production, leading, in turn, to increased E-cadherin production. As a result, the cells stick together and form a tissue-like organization, losing their invasive properties. This finding parallels a recent study in colon cancer patients by pathologists at Erlangen University in Germany. In examining lymph node tumors that had spread from the patient’s colon, the researchers found that some of the cells naturally maintained their invasive character, while others reordered into a crowded, normal “tissue-like” organization. Something about their new environment induced cell repair. This is precisely the process that Ben Ze’ev’s team hopes to promote to block metastasis. The question is how to tilt the scales in favor of the formation of normal tissue.

 “The fact that the invasive process in colon cancer can be turned around is surprising,” says Ben-Ze’ev. “It offers hope of reversing the metastatic process, or even preventing it, in the future. One idea would be to design a drug that would raise the levels of the adhesive E-cadherin protein by targeting its inhibitor - Slug.”  

Prof. Ben-Ze’ev’s research is supported by the M.D. Moross Institute for Cancer Research; the Yad Abraham Center for Cancer Diagnostics and Therapy; the estate of Maria Zondek; and La Fondation Raphael et Regina Levy. He is the incumbent of the Samuel Lunenfeld-Reuben Kunin Professorial Chair of Genetics.

Weizmann Institute scientists have destroyed malignant tumors in mice using a chemical that occurs naturally in garlic. The key to the scientists’ success lies in the development of a two-step system that delivers the cancer-treating chemical directly to the tumor.

The active chemical, called allicin, is the substance that gives garlic its distinctive aroma and flavor. For many years, scientists studying allicin have known that it is as toxic as it is pungent. It has been shown to kill not only cancer cells, but the cells of disease-causing microbes and even healthy human body cells. Fortunately for our cells, allicin is highly unstable and breaks down quickly once ingested. However, its rapid breakdown and undiscriminating toxicity have presented twin hurdles to creating an effective allicin-based therapy. 

Researchers in the Institute’s Biological Chemistry Department have now solved this double challenge, designing a delivery method that works with the pinpoint accuracy of a smart bomb. The study, reported in Molecular Cancer Therapeutics, was performed by Drs. Aharon Rabinkov, Talia Miron and Marina Mironchick, working with Profs. David Mirelman and Meir Wilchek.

Allicin is not present in unbroken cloves of garlic; it is produced in a biochemical reaction between two substances stored apart in tiny adjoining compartments within each clove - an enzyme called alliinase and a normally inert chemical called alliin. When the clove is damaged - whether by food-seeking soil parasites or upon crushing in cooking - the membranes separating the compartments are ruptured, alliin and alliinase interact, and allicin is produced.

The scientists wondered whether it might be possible to reproduce this natural reaction at the site of a tumor. In this way, toxic allicin molecules could be aimed directly at the cancer cells.

To pursue this goal, the scientists took advantage of the fact that most types of cancer cells exhibit distinctive receptors on their surfaces. They took an antibody naturally programmed to recognize one of these receptors and chemically bonded it to the garlic enzyme, alliinase. They then injected this paired unit into the bloodstream, where, as expected, it proceeded to seek out cancerous cells. The second component, alliin, was then injected at intervals. When encountering the alliinase enzyme, the normally inert alliin molecules were turned into lethal allicin molecules, which then penetrated and killed the tumor cells. Neighboring healthy cells remained intact due to the precise delivery system.

Using this method, the team has succeeded in blocking the growth of gastric tumors in mice. The tumor-inhibiting effects were seen up to the end of the experimental period, long after the internally produced allicin was spent. The scientists note that the method could work for most types of cancer, as long as a specific antibody could be customized to recognize receptors unique to the particular cancer cell. The technique could prove invaluable for preventing metastasis following surgery. “Even though doctors cannot detect where metastatic cells have migrated and lodged themselves,” says Mirelman, “the antibody-alliinase unit should be able to hunt them down and, in the presence of alliin, destroy them anywhere in the body.”

From vampires to fungi

Long hailed as a wonder plant, garlic has been used traditionally for everything from warding off vampires to treating bacterial and fungal infections. The ancient Egyptians fed garlic to their pyramid-building slaves to enhance their stamina; the Greeks used it to treat bladder infections, leprosy and asthma; and in World War I, following research by Louis Pasteur proving garlic’s anti-bacterial properties, the plant was used to disinfect open wounds and prevent gangrene.

Modern research has confirmed that garlic has antibacterial, antiviral, antifungal, anti-amoebic, anti-inflammatory and even heart-protecting properties, with a lipid-lowering effect that prevents the accumulation of fatty deposits. Allicin, the active compound in crushed garlic, has been shown to kill over 20 types of bacteria, including Salmonella and Staphylococcus.

In previous research, Prof. Mirelman and his colleagues Dr. Miron, Dr. Rabinkov and Prof. Wilchek revealed that allicin kills disease-causing amoebas, bacteria and fungi by inactivating some of their enzymes. This finding led to current efforts to develop therapies against intestinal and fungal diseases, which claim the lives of thousands yearly and afflict millions more. The group has also shown that allicin can function as an antioxidant, inactivating harmful oxygen molecules believed to contribute to atherosclerosis.

Party planners may have one more thing to worry about in planning their event. To the list of volcanoes, sunspots and other phenomena known to affect the weather, scientists have now added another potential element: ocean plankton.

Though tiny, these ocean-floating organisms may influence weather patterns all over the world, particularly in the tropics. Dr. Hezi Gildor of the Institute’s Environmental Sciences and Energy Research Department revealed this potential link through computer models he designed to examine how nature’s complex web of interacting elements determines global climates.

Plankton drift with ocean currents. They range in size from the microscopic to the barely visible, but they are so abundant their populations can be tracked from orbiting satellites. NASA tracks plankton because they make up the bottommost levels of the marine food chain, and the health of the entire ocean may depend on them.

One of Gildor’s models involves two major groups of plankton: plant-like phytoplankton, which, like their rooted cousins, take up sunlight, carbon dioxide and nutrients and convert them into sugars using chlorophyll; and zooplankton, animal-like organisms that live off the phytoplankton. Under certain conditions, the predator population grows at the expense of its prey until the latter’s dwindling amounts can no longer sustain it. At this point, the zooplankton population drops and its prey (phytoplankton) bounces back, and so on. These repeating cycles, or predator-prey oscillations, can be described mathematically.

Oscillation patterns are seen in global climate systems as well. The western Pacific Ocean is a case in point. The amount of rainfall in this tropical region swings through a cycle every 40-50 days, and the temperature of the surface water beneath oscillates in a more or less corresponding cycle. (Interestingly, even small rises in this region’s oceanic surface temperature can affect weather all across the globe, leading, through a complicated set of interactions, to such far-flung climatic phenomena as rain in India or floods in South America.)

Gildor and colleagues at Columbia University in New York wondered whether these two cycles - of oceanic temperature levels and plankton populations - might somehow be connected.

Their key clue was the phytoplankton’s chlorophyll. Built to absorb light, chlorophyll can block a portion of the warming sunlight that penetrates the ocean’s surface. When conditions are right, plankton congregations can be so dense they effectively shade the water below. Therefore, changes in phytoplankton numbers could affect sea water temperatures.

To test their theory, the team put together a complex simulation based on existing models of three dynamic systems: the atmosphere, ocean water and plankton. They then ran the model to simulate ten months of weather over the tropical Pacific, alternately with and without the plankton component, to see if there were any differences between the two situations.

Their study suggested that the plankton cycle interacts with changing atmospheric conditions, such as cloud formation. Clouds disrupt the normal flow of energy from the sun into the water and from the water back out toward space. As a result, cloud formation affects weather stability along a simple scale: When the level of cloud interference in the atmosphere is low, weather patterns tend to be stable (characterized by un-changing rainfall levels), whereas a high level of cloud interference is characterized by increased instability, in which the system swings between periods of heavy rainfall and clear skies.

But put the phytoplankton into this equation and the scales shift even further. Gildor showed that at the mid-cloud range, where the weather is usually stable, the presence of phytoplankton (due to the natural “ups” of its population cycle) affects the system, driving it toward increased instability. Moreover, as the level of cloud interference rises into the realm of instability, the plankton further influence rainfall patterns, significantly cutting the transition period from clear skies to rain. “It turns out that not only the flap of a butterfly’s wings in Brazil can set off a tornado in Texas, but plankton in the Western Pacific can cause rain in India,” says Gildor.

Cracking the Ice Age

In other research, Gildor applies computer models to examine the history of ice ages on Earth. In the “Sea-Ice-Switch” model, developed together with Prof. Eli Tziperman of the same department, ice forming on the ocean’s surface was found to play a major role in regulating the switch from climatic heating to cooling and back.

Such models are judged by how well they explain existing climate records. Gildor and Tziperman have successfully used the model to explain the mechanism that makes ice sheets advance and retreat; why recent ice ages took place in cycles of 100,000 years, whereas over a million years ago the cycles lasted only 41,000 years; and why CO₂ levels in the atmosphere decreased as the ice advanced.

Dr. Gildor’s research is supported by the Sussman Family Center for the Study of Environmental Sciences and the Sir Charles Clore Prize - the Clore Foundation.