The Math of Distortion

English
 
Many of us in the modern world spend a good part of our day viewing 2-D representations of the 3-D world: drawings and photos, television and electronic screens, to name a few. Our brains automatically translate what we see into three dimensions. Not just that, but we unthinkingly group objects together, identify people from their photos no matter how they are posed, and gauge distances between objects. To the average computer, however, images are basically collections of colored dots in a 2-D grid. One of the bigger challenges for today’s computer scientists is to get these machines to relate to the 3-D world portrayed in their 2-D files as humans do – by sorting, classifying, comparing and inferring.
Dr. Yaron Lipman
 
Dr. Yaron Lipman, who joined the Weizmann Institute’s Computer Science and Applied Mathematics Department in 2011, deals with the mathematics of deformation – variations in shape between similar objects or in that of a single body as it turns, twists, stretches or bends. His work has implications for fields as far-ranging as biology and computer-generated animation, engineering and computer vision.

One of the more basic questions is: In a group of objects, how does one decide whether any two are the same or different? This is not a trivial question, even for humans: To the untrained eye, for example, a pile of old animal bones may be a collection of similar objects, but a trained morphologist or paleontologist will be able to sort them into different species. That ability often comes with years of practice and, just as the average person can tell a pear from an apple without much thought, the expert can distinguish between bones without consciously tracing each step leading up to a particular identification. How, then, does one translate this type of thinking, which is at least partly unconscious, to a mathematical computer algorithm?

Lipman and his colleagues developed an algorithm for comparing and classifying anatomical surfaces such as bones and teeth by analyzing plausible deformations among their three-dimensional models. While a human working from a subjective point of view might look for identifying “landmarks” – for example a specific type of recognizable ridge or protrusion – the computer would take a different track: matching the surfaces globally while minimizing the amount of distortion in the match. A human often works from the bottom up, looking for local cues and then putting them together to arrive at a conclusion. In contrast, the algorithm is designed to consider the collective surfaces as a geometric whole and match them in a top-down manner. Lipman then gave his algorithm the ultimate test – pitting its bone and tooth identification against that of expert morphologists. In all the tests, the computer performed nearly as well as the trained morphologists. That means, he says, that non-experts could use the algorithm to quickly obtain accurate species identification from bones and teeth. In the future, further biological information might be more easily extracted from shape.
 
Matching surfaces: (Top) the computer analysis and (bottom) the points selected by an expert. Note the similarities between the computer’s final result (top right) and that of the expert
 
 
expert match
 
 
 
A second line of research in Lipman’s group is the distantly related problem of image matching. In recent years, as digital cameras are found in every pocket and purse, vast numbers of images are recorded and uploaded to visual media every day. This makes one of the great challenges of computer vision — the ability to interpret, analyze and compare image content automatically – more pressing than ever. In contrast to surfaces, images contain many local cues and features that are easy for a human brain to grasp for recognition. A computer, however, would assign all the points in the image equal importance. So a pair of photos taken with different lighting or from different angles, which a human would have no trouble identifying as the same person, might confound a computer’s point-matching algorithm. Lipman’s solution is to introduce an algorithm for distortion – that is, to determine a mathematical distortion limit on the ways that one set of points can morph into a second set. Somewhat surprisingly, this technique eliminates most of the false matches.
 
Image matching: (top) two images of the same person in different pose; (middle) a set of matching points with no distortion algorithm applied; (bottom) with the distortion algorithm, most of the false matches are eliminated
 

 

 
Yet another train of investigation Lipman pursues is that of modeling mappings and deformations, in 3-D space, of objects that possess desired geometric properties. This area is relevant to computer-generated animation, whose practitioners are constantly in search of better methods for creating life-like motion on screen; engineering, in which computerized models of objects are deformed and mapped to each other; and such areas as medical imaging and computer modeling. Such mappings are laid out on top of a representation of the object as a sort of 3-D mesh of tetrahedrons, and they are then used to work out how the various parts of the mesh deform as the object moves. In real life, this movement involves many parameters, including flexibility, elasticity, movement patterns of joints and the sites where surfaces meet. Lipman develops particular models of deformations that are able to avoid high distortion and self-penetration of matter — both properties of great importance for modeling deformations in “real-life” applications.
 
Applying a standard deformation technique to a 3-D mechanical model (left) produces high distortion and fold-overs (middle, highlighted in red and yellow), which leads to the unstable behavior of numerical algorithms; (right) deformation with strict distortion limits guarantees that the map is free of fold-overs and of bounded distortion
 
 

Dr. Yaron Lipman's research is supported by the Friends of Weizmann Institute in memory of Richard Kronstein
 

 

 

 
Dr. Yaron Lipman
Math & Computer Science
English

Nobel Prize in Chemistry 2009

English
Prof. Ada Yonath. At the Peak
 
 
The Nobel Prize in Chemistry was awarded on December 10 to Prof. Ada Yonath of the Weizmann Institute of Science. Prof. Yonath is the first woman to receive a Nobel Prize in Chemistry in the past 45 years, and only the fourth in the prize’s 108-year history. The prize, which was received jointly by Yonath and Profs. Thomas Steitz of Yale University and Venkatraman Ramakrishnan of Cambridge, was awarded “for studies of the structure and function of the ribosome.” This achievement, obtained with advanced research methods developed by Prof. Yonath, will aid, among other things, in the design of new and better antibiotic drugs.
 
Prof. Ada Yonath was born in Jerusalem in 1939. She completed her undergraduate and M.Sc. studies at the Hebrew University of Jerusalem, and her doctoral work was carried out at the Weizmann Institute. After completing postdoctoral research in the US, Yonath returned to the Weizmann Institute in the 1970s to join the Faculty of Chemistry. There, she established the first (and for almost a decade the only) biological crystallography laboratory in Israel for solving protein structures. Yonath has received many honors and awards for her work, including the Israel Prize in 2002 and the Wolf Prize in 2007.
 

Statements by Weizmann Institute of Science's President Prof. Daniel Zajfman and Nobel laureate in chemistry 2009 Prof. Ada Yonath
 
 

Protein factories

 
 
 
 
At the end of the 1970s, Yonath was a young researcher at the Weizmann Institute with an ambitious plan to settle one of the major outstanding questions concerning living cells: She wanted to determine the three-dimesional structure of the ribosome – the cell’s factory for translating into proteins the instructions written in the gene code – and thus to reveal the mechanics guiding the process. This was the beginning of a long quest – one that would take decades and in which she would be met with reactions of disbelief and even ridicule in the scientific community. In her Nobel lecture, Yonath compared her journey to climbing Mt. Everest “only to discover that a higher Everest stood in front of us.” She began her work in collaboration with Prof. H. G. Wittmann of the Max Planck Institute for Molecular Genetics in Berlin, who supported her studies academically and financially, in parallel to maintaining her modest lab at the Weizmann Institute with an even more modest budget. Yonath came, over the years, to lead a large team of researchers from all corners of the globe. Though her research began as an attempt to understand one of the fundamental components of life, it has led to a detailed understanding of the actions of some of the most widely prescribed antibiotics. Her findings may not only aid in the development of more efficient antibacterial drugs, they could give scientists new weapons in the fight against antibiotic-resistant bacteria – a problem that has been called one of the most pressing medical challenges of the 21st century
 
Almost all the functions of every living organism are performed by proteins, which carry out the daily processes of life. Each protein is made up of a sequence of building blocks called amino acids, and their sequence, which is encoded in the genes, determines how that protein will fold up into the three-dimensional structure it needs to carry out its assigned task. The ribosome is a sort of machine that can make any protein, fashioned according to the code fed into it. The machinery is composed of two subunits – one large and one small – that exist independently but come together to form a functional complex specifically for the task of producing proteins.
 
Because the ribosome is so central to life (not to mention interesting), scientists around the world had been trying for many years to figure out how it works; but without an understanding of its spatial structure, there was little hope of forming a comprehensive picture of its actions. To reveal the three-dimensional structure of such small entities as biological molecules – too small to be seen even under an electron microscope – scientists first turn them into crystals and then bombard the crystals with powerful X rays. The shapes of the crystallized compounds are revealed in the patterns of radiation scattered from them, each unique pattern resulting from the compound’s internal chemical composition. With such X-ray crystallography techniques, one can “map” the distribution of the electrons in the investigated molecule and deduce its structure. But when dealing with ribosomes, there are additional challenges: The ribosome is a complex of proteins and RNA; its structure is extraordinarily intricate; it’s unusually flexible; it’s unstable; and it lacks internal symmetry, a feature that makes the crystallization of even the subunits an extremely formidable task.
 
 

Making crystals

At the beginning of the 1980s, Yonath – working in both the Weizmann Institute in Israel and the Max Planck Institute in Germany – created the first ribosome crystals in the world. The procedure, which she developed especially for this purpose, included a method for the preparation of the crystallizable ribosome that had been developed at the Weizmann Institute by Profs. Ada Zamir, Ruth Miskin, Nahum Sonenberg, David Elson and Meir Wilchek. Her inspiration, she says, came from an article on polar bears: “Polar bears pack their ribosomes in an orderly way in their cells just before hibernation, and these stay intact and functional for months. I said: ‘If polar bears know how to do it, we can do it too.’” She was able to produce the first ribosome crystals in a fairly short time. The early images she managed to obtain, however, yielded only the fuzziest picture, and were not sufficiently detailed to explain the workings of the ribosome.

Yonath was also the first to visualize the tunnel running through the active ribosome, through which the nascent protein progresses as it’s being formed – until it’s big enough to take on a three-dimensional structure and “look after itself.” In the course of her research she developed a number of new techniques that are today widely used in structural biology labs around the world. One of these is cryo bio-crystallography, which involves exposing the crystal to extremely low temperatures – -185° Celsius – to prevent the structure’s disintegration under the X-ray bombardment. She also developed a unique experimental system based on ribosomes taken from the hardy bacteria living in the extreme environments of the Dead Sea, thermal springs and atomic piles.
 
By the end of the 1990s, Yonath had succeeded in breaking the resolution barrier, thanks to improvements both in the crystals and in the facilities for detecting the X-ray diffraction. The result was the first “electron density map” of the ribosome’s small subunit. This is the piece of the ribosome that does the actual job of decoding the gene code, which it reads from a strand of messenger RNA. Her findings were published in 1999 in the Proceedings of the National Academy of Sciences (PNAS), USA. Then, in 2000 and 2001, Yonath published the first complete three-dimensional structure of both subunits of a bacterial ribosome – work that was hailed by Science magazine as one of the ten most important breakthroughs of the year.
 
These discoveries were clearly a high point in 20 years of research. But Yonath’s quest to understand the ribosome was far from complete. Armed with new insight into ribosomal structure, she moved on to revealing what that structure can tell us about its actions and, especially, how antibiotic drugs block those actions in bacterial ribosomes. Another challenge Yonath and her research team undertook was to try to understand how cellular factors initiate the process, “telling” the ribosome that it must begin protein assembly. To produce an image of the contacts with one such cellular factor, Yonath and her colleagues inserted a component into the crystal that attaches to the ribosome and activates it.
 
 

Drug effects

 

 
 
 
Because ribosomes are so essential to life, it makes sense that many antibiotic drugs work by targeting their actions. “The advances we made in our long quest to solve the structure and function of the ribosome may pave the way toward better antibiotic drugs,” says Yonath. Together with team members Dr. Anat Bashan, research student Raz Zarivach and scientists at the Max Planck Institute in Germany, she crystallized bacterial ribosomes, each with one of five antibiotic compounds bound to it. They found that the drugs tended to bind in specific “pockets” in the structure, preventing the ribosomes from manufacturing proteins and eventually killing the bacteria. Since these findings were published in Nature, in 2001, Yonath has revealed the mode of action of several more common antibiotics, and her research in this area is ongoing. Yonath: “Most antibiotic drugs bind to one active site or another in the ribosomes, paralyzing them and preventing them from making the proteins necessary for bacterial life. With our understanding of protein manufacture, we can now design antibiotics to attack bacteria that have developed resistance to the existing drugs.”
 
Another line of research – conducted in collaboration with Profs. Lou Massa of City University of New York and Nobel laureate (1985, Physics) Jerome Karle of the Naval Research Laboratory in Washington – used a method called “quantum crystallography” to observe the process of protein assembly in real time.
 
Planning her future research, Yonath intends to look to the distant past. Ribosomes are found in every living being – from yeast and bacteria to mammals – and the structure of their active sites has been extraordinarily well-preserved throughout evolution. Could a pared-down, primordial ribosome have begun producing the first proteins hundreds of millions of years ago, essentially giving rise to life? How did these first ribosomes come into being? How did they begin to produce proteins? How did they evolve into the sophisticated protein factories we see today in living cells? Yonath plans on answering these and other questions in her future work.

 
Prof. Ada Yonath’s research is supported by the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly. Prof. Yonath is the Martin S. and Helen Kimmel Professor of Structural Biology.
 
 
Prof. Yonath was asked to deliver the Nobel banquet speech in the name of the three Chemistry laureates. The following is the text of that speech:

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,
It is a great honor for me to be able to express my sincere gratitude to the Nobel Foundation.
 
I was asked to represent the 2009 Chemistry laureates, who are three different people. We belong to different nationalities, genders, views and upbringings. However, we share a common passion: to understand how the ribosome makes proteins according to the instructions of the genetic code, an issue to which many more scientists around the world have contributed tremendously.
 
When I was approached by the Royal Academy, I was advised to benefit from the speech given by Isaac Bashevis Singer, the 1978 Literature laureate, who started with: “People ask me often, ‘Why do you write in a dying language, Yiddish?’”
 
Indeed, words originating from the verb “to die” were frequently used when I described my initial plans to determine the ribosome structure. Many distinguished scientists said: “Why work on ribosomes, they are dead… we know all what can be known about them,” or: “This is a dead end road,” or: “You will be dead before you get there.” To my satisfaction, these predictions were proven wrong, the ribosomes are alive and kicking (so am I) and their high-resolution structures stimulated more advanced studies as well as the imagination of many youngsters, including my granddaughter, Noa, who is showing continuous interest, and invited me at the ages of 5 and 13 to explain to her classes what the ribosome is. Also, there is a new saying in Israel: Curly hair (like mine) means ROSH MALEH RIBOSOMIM, which translates to: head full of ribosomes. Furthermore, our studies added to the buzz around the lovely polar bears, which inspired my own research and are now endangered by the changing climate.
 
I was also instructed not to use this opportunity for thanking. I have always been known as an obedient person, and thus decided to follow this advice too, but with one exception. I want to thank warmly my dedicated chauffeur, Nisse. Without him I would have been lost in Stockholm, the wonderful, albeit dark city, and consequently miss most of the fascinating events of this magic week.

 

Prof. Ada Yonath

Prof. Ada Yonath

 

First Experiment

First Experiment

 

As a young child, Prof. Ada Yonath lived in a four-room apartment that her family shared with another three families and their children. Hard conditions didn’t dampen her enormous curiosity, though. Already at five, she was actively investigating the world around her. She tried to measure the height of their tiny balcony using furniture from inside the apartment. She put a table on another table and then a chair and a stool on top, and when she climbed up on her structure, she fell and broke her arm. In this photo from her kindergarten class, Ada (standing, center) has her arm in a cast.

 

 

It Takes a Research Team

On January 26, Prof. Yonath had

On January 26, Prof. Yonath had a chance to celebrate with her research team. The group went to the Druze town of Daliyat al Carmel, near Haifa, for the day. There they received a tour and an explanation of the Druze faith, as well as lunch in one of the town’s fine restaurants

 

Meeting with Iranians

Meeting with Iranians

In November, just three weeks before the Nobel Prize award ceremony, Prof. Yonath had no time to even think about the upcoming event. She had flown from Boston to the European Synchrotron research facility in Grenoble, France, and then to Ben-Gurion Airport. From there, she flew to Amman, Jordan, where she immediately caught a taxi to the ancient city of Petra or, rather, to the modern hotel next door, for a conference. Though Yonath has had to turn down hundreds of requests for her time since the announcement, this was one she couldn’t say no to: a meeting of researchers working on the SESAME Middle Eastern synchrotron project, based in Jordan. The project, which will only be fully operational in 2013, brings structural biologists from the region, from Egypt to Iran, together to discuss their latest work. After Yonath’s lecture, she was surprised to find the Iranian delegation waiting for her, especially a headscarfed young researcher who only wanted a minute to hug Yonath and tell how much her life story meant to her, an Iranian woman.

 

Chemistry
English

Fine China

English

Weizmann-Chinese archaeology team in Hunan

 

 

 

 

 

 
 
 
 
 
 
 
 
 
 
 
China gave the world porcelain: The name of the country is synonymous with elegant ceramic dinnerware. But did China also give the world its first clay pottery? Until now, there have been several contenders for that title, most notably Japan and eastern Russia. Now, Dr. Elisabetta Boaretto of the Helen and Martin Kimmel Center for Archaeological Science and Bar-Ilan University, and Prof. Stephen Weiner, Head of the Kimmel Center in the Weizmann Institute’s Faculty of Chemistry, along with an international team of researchers, have conclusively dated the most ancient pottery yet discovered to more than 18,000 years ago. This gives the award for the earliest known use of ceramic technology to the prehistoric residents of the Hunan region in southern China. The findings, which were recently published in the Proceedings of the National Academy of Sciences (PNAS), USA, show that clay pottery was being produced at least 1,000 years earlier than previously thought.
 
“Humans have used fire for around a million years, but it was just a ‘short while ago’ – less than 20,000 years – that they discovered how to bake clay-rich soil into vessels,” says Weiner. It was a technological feat that took place even before the era of great social and economic change accompanying the transition to permanent agricultural settlement known as the Neolithic. Up to now, however, dating either the sediment layers or the pottery and other artifacts found in ancient caves has been next to impossible. Standard dating techniques based on radioactive carbon have not produced reliable results, mainly due to the difficulty of finding well-preserved datable material.
 
Boaretto, Weiner and their colleagues tailored a new, multi-pronged approach to overcome these difficulties. First, they learned the layout of the Yuchanyan Cave in Hunan Province in detail, including each of its archaeological strata, before assembling a large collection of charcoal fragments and bones – about 150 altogether – for testing. Because the pottery can’t be directly dated, they paid special attention to samples from layers in which clay shards were also found. “The accepted method is to take as many datable samples as possible; but we chose a different approach,” explains Boaretto. She developed a strict system of “quality control” to sort the samples. Using an infrared spectrometer, the team identified the ones most likely to yield reliable data. Only samples that contained original carbon and hadn’t been contaminated with foreign carbon were used to date the various strata.
 
About 40 of the samples proved to be clean and well preserved, and these were subjected to radiocarbon dating. To confirm their analysis and check the fit between the radiocarbon dating of bone and charcoal and the age of the pottery vessels buried in the cave, the research team carried out extensive mapping of the cave’s strata and a micro-morphological analysis of its sediments. By the time they were done, they had produced a consistent sequence of dates for human presence in the cave, including ages for the pottery found there. The most ancient clay vessels were found to be around 18,300 years old – the oldest ever discovered.
 
Since the layers were mostly laid down by human activities – ash from fires, clay used to prepare fireplaces, remains of meals, etc. – the analysis of the cave sediments revealed a bit about the people who lived there. It seems the cave’s inhabitants dined on wild boar, turtles, fish, small mammals, and also wild rice. The Yangtze River basin in southern China was a center of settlement in the Late Paleolithic, and it’s likely that many of the caves in the region were similarly inhabited by such groups in the very early stages of transition from nomadic hunting to agricultural settlement, when they were just beginning to use clay vessels.
 
Although these findings have conclusively dated the earliest known pottery and shed light on the beginnings of human settlement in southern China nearly 20,000 years ago, a number of mysteries remain. For instance, why is there such a large gap between the use of pottery in eastern Asia and its adoption in the West? People in the Levant began producing clay vessels only some 10,000 years later than residents of southern China. Other technologies, in contrast – including the use of bronze and domestication of plants – arose earlier in western Asia. Could this technology have arisen independently in a number of places, or did it begin in China and then gradually spread throughout eastern Asia?

 
Prof. Stephen Weiner’s research is supported by the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research; the Helen and Martin Kimmel Center for Archaeological Science; the Maurice and Vivienne Wohl Charitable Foundation; and the estate of George Schwartzman. Prof. Weiner is the incumbent of the Dr. Walter and Dr. Trude Borchardt Professorial Chair in Structural Biology.
 
Hunan caves near site of ancient pottery
 

 

 
Prof. Stephen Weiner (sitting, second from left) and Dr. Elisabetta Boaretto (standing, fourth from left) with the international team of researchers
Scientific Archaeology
English
Yes

The Woman Who Called Dr. Chaim Weizmann "The Chief"

English
 
Dr. Esther Hellinger in her lab at the Daniel Sieff Research Institute
 


 

Dr. Chaim Weizmann’s letter to Hellinger offering her a position at the Sieff Institute

 
 
The life of Esther Hellinger changed forever with the issuing of the 1917 Balfour Declaration: Then an 18-year-old student of botany at the University of London, she decided that one day she would move to the Land of Israel.
 
Born in London into a family of Jewish immigrants from Latvia, the fourth of nine children, Hellinger had professional goals that were unusual for a woman at the time. She wanted to specialize in plant diseases, particularly those caused by fungi, hoping that expertise in this area would enable her to help develop agriculture in the Jewish National Home. Her lecturer on this subject was skeptical, as she was to recall years later in autobiographical notes: “When I informed [him] of my aspirations regarding plant disease work in Palestine, he was quite blunt. ‘As a woman you stand no earthly chance,’ he said.”
 
Hellinger visited Eretz-Israel for the first time with a group of Jewish British students to attend the opening ceremony of the Hebrew University of Jerusalem on Mt. Scopus, on April 1, 1925. “It was an unforgettable scene which thrilled me to the core,” she wrote later. In 1926, she was back to stay, and she spent five years conducting research on local plant diseases at the Jewish Agency’s Agricultural Experimental Station in Rehovot. One major project, sponsored by Britain’s Empire Marketing Board, focused on the decay of citrus fruits. At the same time, she prepared a thesis on fungal infection in fruit, which in 1931 earned her a Ph.D. from the University of London.
 
It was back in England in October 1932 that Hellinger first met Dr. Chaim Weizmann, who obtained for her a scholarship to receive training in areas of bacteriology particularly useful for Eretz-Israel. She spent more than a year in Europe, mainly in Switzerland, honing her skills in microscopy and microphotography, isolating various bacteria and gaining experience in the bacteriology of milk and soil at different institutions. “I feel now that I could be of use to our bee keepers in their disease troubles,” she wrote to Weizmann after spending two weeks in a bee disease laboratory. In another letter, she reported on her training at a facility specializing in Gruyere and Emmental cheeses, adding that “a certain amount of soft double-cream cheeses are made in Switzerland, but I must confess that I have tasted better in Palestine…”
 
In July 1933, Dr. Weizmann offered Hellinger the position of Chief Bacteriologist and Mycologist at the Daniel Sieff Research Institute about to open in Rehovot. “Nothing could please me better!” Hellinger promptly wrote back. At the end of March 1934, after a five-day trip by boat from Marseilles to Jaffa, she arrived in Rehovot just in time for the inauguration of the Sieff Institute on April 3. Its staff of 11 scientists included four women, an unusually high percentage for those days.
 
Old-timers remember Hellinger, a petite woman with curly hair, as modest, friendly and talkative; she knew Hebrew but preferred to speak English. To the sabras, she seemed typically British: she had perfect manners, spoke in understatements and never showed excitement.
 
Much of Hellinger’s early work at the Sieff Institute, aimed at boosting the chemical industry in Eretz-Israel, focused on new uses for the sugar-containing waste products of the dairy industry. In the late 1930s, she registered two patents: on improving chicken feed and on making use of milk whey by fermentation.
 
In the early 1940s, she twice earned what at the Sieff Institute was considered a special honor – co-authoring scientific papers with Chaim Weizmann, whom she called “The Chief.” Both papers elaborated on Weizmann’s famous fermentation method, which had been used to produce acetone from maize during World War I. Thanks to the new Sieff Institute research, a factory near Tel Aviv produced acetone and butyl alcohol, this time needed in World War II, by fermenting orange peel.
 
After the establishment of the State of Israel, Hellinger collaborated with scientists from the Research Council of Israel, who sought to revive the cultivation of flax, commonly grown in the area in antiquity. Hellinger helped them develop an improved method of flax retting – the process of separating flax fibers from the stem using bacteria – which for about a decade was applied at a factory in Kiryat Malachi.
 
Upon retiring from the Weizmann Institute in 1955, Hellinger, who never married, had no family in Israel and had trouble adjusting to the local climate, moved back to London to be close to her brothers and sisters. In a news item about her retirement, the journal Nature described her as “one of the band of enthusiastic scientists who have done so much for plant pathology and industrial mycology in Israel.”
 
While working at the Marks and Spencer’s Analytical Laboratory in London, Hellinger collaborated with a Weizmann Institute team that developed a wax coating to prevent the rotting of citrus fruit exported from Israel. When the method was commercialized, Hellinger – perhaps remembering the scholarship that got her started on her own career – used her share of the royalties to create a fund in support of students at Weizmann.
 
In 1978, at the meeting of the Weizmann Institute’s Board of Governors, Hellinger was presented with a scroll of appreciation, “in grateful and affectionate recognition of her unique personal dedication to this Institute, with which she has been so effectively and fruitfully associated ever since – at Dr. Chaim Weizmann’s request – she joined the pioneering scientific staff of the Daniel Sieff Research Institute.” She passed away in London four years later, at age 82.
 
Now, each year, the Weizmann Institute continues to award the Dr. Esther Hellinger Memorial Scholarship to a doctoral student enrolled in its Feinberg Graduate School.
 
We are grateful to the Weizmann Institute of Science Archives; the Weizmann Archives; Executive Director of Weizmann UK Sheridan Gould; Dr. Hellinger’s niece Anne Weyman and nephew Simon Cheifetz, both of London; Nahum Ben-Yehuda, CText ATI (Associate of the Textile Institute), of Bar-Ilan University; and all the others who assisted in the preparation of this article
 

Esther Hellinger receives a scroll from Institute President Prof. Michael Sela

 
Dr. Esther Hellinger
English

p53 Turns Thirty

English
 
 
(l-r) Dr. Perry Stambolsky and Profs. Varda Rotter and Moshe Oren
 
In 1979, disco was reaching  its height, Egypt and Israel were negotiating a peace treaty, and cancer researchers were in the midst of the revelation that genes can promote cancer. Certain viruses, for instance those that insert their DNA into the genes of their host cells and others that “borrow” host genes and manipulate them, were found to cause cancer. Almost accidentally, several research groups noted the existence of a gene that seemed to play a role in the cell’s switch to malignancy after becoming infected with  cancer-causing viruses.

Two young Israeli researchers working in the US became involved with the new gene, called p53. (The number refers to the molecular weight. It has since been corrected to 43.7, but the name has stuck.) Moshe Oren was in the Princeton lab of Prof. Arnold Levine – one of those labs that first published the discovery of p53. Meanwhile, Varda Rotter, under the guidance of Nobel laureate Prof. David Baltimore, identified the p53 gene in a different type of virus-caused tumor.
 
That early research seemed to indicate that p53 was an oncogene – a cancer-causing gene. Rotter’s research in Baltimore’s lab revealed high levels of the p53 protein in many types of cancer cells (including those not infected with a virus), but almost none in non-cancerous ones.
 
Oren and Rotter both returned to Israel in 1981, soon setting up independent labs in what would become the Weizmann Institute’s Molecular Cell Biology Department, and they began to study the gene in earnest. Quantities of DNA were needed for experiments, and this meant that the gene had to be cloned – a procedure that in those days required, says Oren, “a lot of improvisation, ingenuity and (not least) good luck.” Oren, beginning his work in the lab of Prof. David Givol and continuing to collaborate with Levine, was the first to clone the p53 gene, in 1983. Givol has since joined the circle of p53 researchers, with numerous contributions of his own. Rotter, continuing the work she started in the US, developed new methods for detecting p53 in cells – methods that are in use today in hundreds of labs around the world. In 1983, she suggested that the p53 protein can be regarded as a “tumor-specific marker.”
 
The two scientists enjoyed a sort of “friendly, constructive competition.” In that first decade p53 research began to take some interesting twists and turns. Sometimes the gene clearly played a role in cancer, but in other cancer cells it was inactivated, and results from different clones didn’t always match. In 1989, Oren, Rotter and others compared the various p53 clones and discovered they were all different; what they had thought were oncogenes were in fact mutated versions of a gene that in healthy cells normally plays an entirely different role.
 
It soon became apparent that unmutated, healthy p53 is the opposite of a cancer gene – it’s a tumor suppressor that prevents renegade genes from driving the cell toward cancer. Sir David Lane, one of p53’s codiscoverers, dubbed it “the guardian of the genome.” Just as significant were discoveries that p53 is mutated in about half of all cancers and its actions stymied in many others. With that, p53 research took off. But just when it seemed that this one gene might hold the answer to how cancer develops, scientists began to discover how many complex roles that gene can play. To date, over 50,000 scientific papers have been published on p53, and the flow of new discoveries has by no means abated.
 
While the research of Profs. Oren and Rotter diverged – he turned more to unraveling the role of unmutated p53 in healthy cellular function, she to investigating mutated p53 in cancer – they also began to collaborate. To date, they have published 15 joint papers (see box). They have received numerous awards for their pioneering work, and each of them was recently honored with an invitation to contribute to a special issue of Nature Reviews: Cancer, commemorating 30 years of p53 research.
 
Was it worthwhile for one small institute to support two groups conducting cutting-edge studies on the same gene? Oren and Rotter say the synergy between them has generated a critical mass that has put the Weizmann Institute and Israel at the forefront of p53 research. They emphasize that at least 20 Weizmann research teams are involved in p53-related research; and the younger generation of scientists is using new methods to address as yet unanswered questions. Indeed, there is hardly a cancer researcher around who hasn’t investigated p53 in one way or another.
 
Prof. Moshe Oren’s research is supported by the M.D. Moross Institute for Cancer Research.
 
Prof. Varda Rotter’s research is supported by the Leir Charitable Foundations; the Centre Leon Berard Lyon; the Lombroso Prize for Cancer Research; the Jeanne and Joseph Nissim Family Foundation for Life Sciences; the estate of John M. Lang; and Donald Schwarz, Sherman Oaks, CA. Prof. Rotter is the incumbent of the Norman and Helen Asher Chair of Cancer Research.
 

When to Skip the Vitamins

Vitamin D may have cancer-prevention properties. But can it help if a person is already ill? Clinical trials examining the effects of vitamin D on patients receiving chemotherapy have not yet answered this question. But Profs. Oren and Rotter’s latest collaborative effort, conducted with former student Perry Stambolsky, began from a different angle altogether: Two unrelated experiments in their labs seemed to point to a connection between p53 and the molecular machinery mediating the cell’s response to vitamin D. Probing further, they found out exactly how this machinery interacts with p53, providing a sort of booster that reinforces its actions. That’s good news when the p53 is a non-mutated tumor suppressor: Vitamin D can assist in destroying the tumor. It might, however, be a reason for concern when p53 is mutated. Oren: “When healthy, p53 prevents cancer. But mutations are like sticks jamming the machinery that keeps cancer at bay, and vitamin D may wedge those ‘sticks’ into the works a little tighter.” Rotter: “When deciding whether to prescribe vitamin D, it might be important to know not just whether the p53 is mutated, but the nature of those mutations.”
 
 
(l-r) Dr. Perry Stambolsky and Profs. Varda Rotter and Moshe Oren
Life Sciences
English

Preserving the Pristine

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Prof. Emanuel Mazor. Desert formations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most of the southern part of Israel is desert. But that desert is hardly an unvarying expanse of sand and rock. Mountains, gorges, makhteshim (erosion craters) and other fascinating geological formations, as well as unique flora, fauna and history grace the area. To Prof. Emanuel Mazor of the Environmental Sciences and Energy Research Department, the Negev is a treasure chest of pristine landscapes that present both a wealth of research opportunities and a challenge to preserve some of the few remaining undeveloped areas in Israel.
Dead Sea and surroundings

 

Over the past few decades Mazor has used a combination of survey techniques, including satellite imaging, GIS and on-the-ground field studies to map the central Negev in detail. He has identified 35 unique regions, each with its own geology, tectonics, zoology, archaeology and history.

Among the most impressive regions in the Negev is the Ramon area. Mazor was instrumental in persuading the government, some 12 years ago, to turn the area of the Ramon makhteshim into a national park. Thanks to his efforts, this park includes centers both for public education and for scientific research. Mazor is continuing to work for the preservation of Negev landscapes in a number of ways, from helping to curtail polluting mining activity to working with Negev communities to help them connect with their environment.
 

Mt karkom petroglyph

 

This past year Mazor was awarded several prestigious prizes in recognition of his achievements: a Lifetime Achievement Award for Environmental Protection from the Israel Ministry of Environmental Protection, a Magshim (implementer) Award from the Council for a Beautiful Israel, and a medal for his outstanding contribution to public awareness of the earth sciences awarded by the Israel Geological Society.

 
Prof. Emanuel Mazor. Desert formations
Environment
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Past Perfect

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Dr. Ruth Shahack-Gross. archaeology of animals

 

 

 

 

 

 

 

 

 

 

The present can supply us with intriguing glimpses into the past. In geology, for example, long-term processes that continue to this day can shed light on those belonging to the distant past. The same principle guides ethno-archaeologists, who study today’s traditional societies to learn about the lifestyles of ancient cultures. Dr. Ruth Shahack-Gross, who began her research career as a geologist, became captivated by this approach when she turned to archaeology: “I was immediately fascinated by the idea of learning about the past from contemporary traditional lifestyles,” she says.

In her studies in Kenya, Shahack-Gross used the geo-ethno-archaeological approach to identify ancient livestock enclosures. Accompanied by a Maasai tribe elder, she collected soil samples from his village and from a series of abandoned villages in which he had lived in the past. In this manner, she managed to create a “time axis” describing the breakdown of organic matter over 40 years. Under the guidance of Prof. Stephen Weiner of the Weizmann Institute’s Helen and Martin Kimmel Center for Archaeological Science, she developed a method for identifying livestock premises using a variety of soil analyses and microscopic tests, including an analysis of phytoliths – tiny silica particles present in many grasses, including animal feed, that end up in cattle dung. An analysis of phytoliths and additional minerals allows her to identify livestock enclosures long after organic matter – a more direct but less stable evidence of their presence – has disintegrated.

Shahack-Gross then joined a Kimmel Center team at the excavations in Tel Dor, where she got an opportunity to apply her method. Together with collaborators from Israel and Spain, she showed that the white-powdered surfaces in the excavated town were collections of phytoliths originating in the dung of livestock kept in enclosures within the city (and not from man-made plaster floors, as had been believed earlier). She also found evidence that animal dung had been used as fuel. These findings suggest that today’s clear-cut divide between agricultural and urban settlements came into being later than previously thought, providing new insights into the nature of the so-called “urban revolution” thought to have occurred in antiquity in the Mediterranean region.

Shahack-Gross, a senior lecturer in the Department of Land of Israel Studies and Archaeology at Bar-Ilan University, joined the Kimmel Center as a visiting scientist as part of a joint program initiated by Weiner. She uses a variety of analytical methods – infrared spectroscopy and oxygen and carbon isotope geochemistry, as well as microscopy – to identify the phytoliths and other materials in soil and ash samples. These methods allow her to gain new information about ancient societies, including the types of food consumed by their cattle. “Today hardly any archaeological excavations are conducted without backing from the natural sciences,” she says.

In another ethno-archaeological study, conducted with Prof. Israel Finkelstein of Tel Aviv University, she used analysis of materials, including phytoliths, to help solve a controversy over settlements created in the Negev Highlands during the Iron Age, corresponding to the Biblical period of Kings (circa 1,200 – 600 BCE). One opinion, based on the Bible, states that certain buildings are remains of fortresses built by King Solomon to protect his kingdom from Egypt and that they were destroyed by Pharaoh Sheshonq I during his northern campaign in the late tenth century BCE. Finkelstein, however, claimed that these buildings had been erected by cattle herders, but he relied on “circumstantial” evidence: The so-called “fortresses” were not located at strategic positions and did not have the uniform appearance of military structures.

Shahack-Gross collected numerous ash and soil samples from two sites near Sde Boker. Her analysis revealed traces of goat dung in the central courtyards of these fortresses. The sediments at the Negev Highlands sites were very low in phytoliths, reflecting a diet of wild plants and lichen. In addition, no phytoliths originating in domestic cereals – in other words, in agricultural crops – were found. These results, backed by analyses of sediments in contemporary Bedouin settlements in the Negev, suggest that the residents of the fortresses were indeed shepherds. And the hypothesis that the Iron Age settlements in the Negev Highlands were built as part of the Kingdom of Judea must be reconsidered.

The dating of plant remains using radioactive carbon, conducted in collaboration with Dr. Elisabetta Boaretto of Bar-Ilan University and the Weizmann Institute’s Kimmel Center, showed that these sites were set up in the late tenth century BCE and operated for about 100 years, until the end of the ninth century BCE. “Sheshonq’s campaign might have led to the creation rather than destruction of these settlements,” Shahack-Gross says. “Moreover, evidence suggests that these were seasonal settlements typical of nomadic herders.” In additional analyses, the scientists will try to determine whether these settlements were indeed seasonal and what they were like during the Iron Age.

Prof. Stephen Weiner’s research is supported by the Kekst Family Center for Medical Genetics; the Helen and Martin Kimmel Center for Archaeological Science; the Maurice and Vivienne Wohl Charitable Foundation; and the estate of George Schwartzman. Prof. Weiner is the incumbent of the Dr. Walter and Dr. Trude Borchardt Professorial Chair in Structural Biology.

 
microscopic archaeological samples reveal ancient lifestyles
 

 

 

 

 
Dr. Ruth Shahack-Gross. Looking for ancient livestock
Scientific Archaeology
English
Yes

Prof. Ephraim Katzir 1916-2009

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Institute Professor Ephraim Katzir
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institute Professor Ephraim Katzir, the fourth president of the State of Israel, an internationally esteemed Israeli scientist and one of the founders of the Weizmann Institute of Science, passed away on Saturday, May 30, 2009, at his home in the Weizmann Institute. He was 93.

Ephraim Katzir was born in Kiev, Ukraine, in 1916. His parents, Yehuda and Tzila Katchalski, brought him to the Land of Israel in 1922. After finishing high school in Jerusalem, he chose to study botany, zoology and bacteriology at the Hebrew University of Jerusalem, though he eventually focused on biochemistry and organic chemistry. In 1941, he completed his doctoral degree with research in simple synthetic polymers of amino acids and continued his studies at the Polytechnic Institute of Brooklyn, Columbia University and Harvard University.

While studying in Jerusalem, Katzir was active in the Hagana and advanced to the rank of field corps company commander. In 1948, after returning from the US, he became involved in military research and development in the Israel army’s Science Corps, “Hemed,” founded at the start of the 1948 War of Independence, and for a time commanded it as a lieutenant colonel.

At the close of the War of Independence, together with his scientist brother, Aharon, Ephraim Katzir joined the faculty of the Weizmann Institute of Science where he established and headed the Biophysics Department. Aharon served as head of the Polymer Department until his murder in a terrorist attack at the Lod airport in 1972.

Over the course of his career, Ephraim Katzir researched synthetic models to investigate the principles of polymer structure and function. His pioneering studies contributed to the deciphering of the genetic code, to the development of synthetic antigens, and to the clarification of the various steps in immune reactions. An understanding of the properties of his models (“poly-amino acids”) aided, among other things, in the development of the multiple sclerosis drug Copaxone® at the Weizmann Institute.

Another of Katzir’s significant successes was the development, in the 1960s, of a method for binding enzymes to various substrates. The method is used today as an important tool in the drug and food industries.

Parallel to his scientific research, Katzir was also active over the years in the social and educational sides of science. He headed a governmental committee that set national science policy, raised generations of new scientists, translated important scientific material into Hebrew and helped to establish a Hebrew-language popular science magazine. He served as the head scientist of the Ministry of Defense and chaired the Society for the Advancement of Science in Israel, the Israeli Biochemical Society, the National Council for Research and Development and the Council for the Advancement of Science Education. In addition, he headed the National Biotechnology Council.

In 1973, Katzir was chosen to be president of the State of Israel (its fourth president), a position he held until 1978. (With his appointment to the presidency, he changed his name from Katchalski to Katzir.) In his term as president, he put special emphasis on societal problems and education and regularly went out of his way to become acquainted with all the different groups making up Israel’s population.

Returning to his scientific career, Katzir’s research took off in new directions. He headed a team that won an international competition for computerized modeling of proteins and took part in a multidisciplinary scientific team that discovered key aspects of the effect of snake venom on the human body. He authored hundreds of scientific articles and served on the editorial and advisory boards of many scientific journals. In honor of his 60th, 70th and 80th birthdays, international scientific symposia were held in Rehovot and Jerusalem. On his 90th birthday, an international scientific conference was held at the Weizmann Institute.

Prof. Katzir was a member of the Israel Academy of Sciences and Humanities and of numerous other learned bodies in Israel and abroad, including the Royal Institution of Great Britain, the Royal Society of London, the National Academy of Sciences of the United States, the Academie des Sciences in France, the Scientific Academy of Argentina and the World Academy of Art and Science. He was a visiting professor at Harvard University, Rockefeller University, the University of California at Los Angeles and Battelle Seattle Research Center.

In addition, Katzir was awarded the Rothschild and Israel Prizes in Natural Sciences, the Weizmann Prize, the Linderstrom Land Gold Medal, the Hans Krebs Medal, the Tchernikovsky Prize for scientific translation, the Alpha Omega Achievement Medal and the Engineering Foundation’s International Award in Enzyme Engineering. He was the first recipient of the Japan Prize and was appointed to France’s Order of the Legion of Honor. He received honorary doctorates from more than a dozen institutions of higher learning in Israel and around the world, including Harvard University, Northwestern University, McGill University, the University of Oxford and the Technion – Israel Institute of Technology.

The official memorial ceremony, held in the Weizmann Institute’s Memorial Plaza, was attended by the president of the state, Shimon Peres, Prime Minister Benjamin Netanyahu and Minister of Defense Ehud Barak, as well as many government ministers, Knesset members, educators, scientists and members of the public.
 
President Shimon Peres said in his memory: “I have never met another man with such renown and talents as Ephraim, who had so much personal humility combined with such public boldness; boldness in everything related to science, modesty in everything related to the man. He founded the IDF Science Corps (Hemed). When I was director of the Ministry of Defense, the cooperation between us was both full and stimulating. He always created an atmosphere around him of quiet faith.

“From the state’s beginning, Ben-Gurion wanted the president to be a man of science. After Aharon’s murder, then Prime Minister Golda Meir had a heart-to-heart talk with Ephraim and he agreed to take on the mantle of the presidency. Ephraim had a hard time refusing the request, but it was just as hard for him to tear himself away from his lab. He used his scientific savvy in the role of president, working to unite the people, reduce inequality, prevent the polarization of the society and raise its moral standards, as well as to raise the standard of science.”

Prime Minister Benjamin Netanyahu said in his memory: “There are few people whose humility and common touch become greater as they rise in the world. Not many are the people who, even as they ascend to the summit, continue to act with everyday humanity. Ephraim Katzir was such a man. Even when he was president, he was never high and mighty; even when he led groundbreaking research, he never lost sight of the path beneath his feet; even when his name became known around the world, his love for this country remained steadfast and deep. A gracious man, ethical, deep, inquisitive and a lover of his fellow man. Ephraim Katzir was nobly stoic in the face of the loss of his beloved brother, Aharon, who was murdered at the hands of terrorists.

“His whole life, Ephraim Katzir used his rare abilities to contribute to his people and his country. He always made sure that the mission was the main point and not himself – the instrument of the mission.

“This attitude of quiet, modest contribution noticeably accompanied him even when he was chosen to be the fourth president of the State of Israel. History arranged a term for him that began with the Yom Kippur War and ended with peace negotiations with the largest Arab state – Egypt. Yet in this period, President Katzir managed to devote a good part of his time to issues of society and education, higher education and welfare, and he initiated many important projects and good works. And he was always searching for ways to connect youth with science.”

The president of the Weizmann Institute of Science, Prof. Daniel Zajfman, said in his memory: “Ephraim was a brave scientist, who followed his curiosity to the boundaries of human knowledge. In the days when it was hard to imagine a connection between physics and the life sciences, Ephraim founded the Department of Biophysics at the Weizmann Institute of Science. In the days when the State of Israel was having difficulty feeding its citizens, Ephraim looked into the future and decided to research the structure of proteins and their function in the human body.

“But Ephraim didn’t shut himself up in the lab. He saw science as an integral part of human culture and he believed that scientists should lead human society to a better future. Faithful to this belief, he took an extremely active role in explaining science to the general public and he headed the Council for the Advancement of Science Education.

“In Ephraim’s life, Zionism and science were interwoven. It’s not accidental that this ceremony is taking place not far from the burial place of the first president of the State of Israel and of the Weizmann Institute of Science, Chaim Weizmann. It’s no accident that two Weizmann Institute scientists have served as president of the state: Ephraim Katzir and Chaim Weizmann. Both saw Zionism and science as two sides of a whole that is greater than its parts; both believed in the expansion of human knowledge as a means to improve the quality of life for all. Not only were they both right, they proved the justice of their claim.”


Open Questions


In one of Prof. Ephraim Katzir’s last public appearances, he spoke to a group of young people who were at the Weizmann Institute to hear a science lecture in the Katzir-Makineni Lecture Series.

He said: “As someone who has been involved for years in researching life processes, I believe that young people have the originality of thought and the courage to work in any field they choose to engage in.

“When I started studying at the Hebrew University of Jerusalem, I thought I would be a mathematician. I studied mathematics for a whole year and I got great satisfaction from it because there’s a philosophy to mathematics and pure reason. Afterward, I thought that physics was a good subject and I founded the Biophysics Department. In this field, as well, I enjoyed myself, and I saw that a foundation in mathematics is exceptionally beneficial. When I reached the ripe old age of 40, I decided that the life sciences were interesting – and it is, really, a wonderful field. Thus, if any of you choose to go into mathematics and also want to conduct research, I can promise you one thing: There’s outstanding satisfaction in scientific research and there are many more questions waiting for you to discover and investigate. For example: How does one part of the body affect another part? Why do I think in my head that this place is nice? Why, when I’m hungry, does my stomach suddenly start to tell me I’m hungry? A lot of questions are waiting for you to come and answer them and share your knowledge with everyone.”
 
Katzir brothers and their parents
 
 
Moshe Dayan, Ephraim Katzir and David Elazar
 
 
Katzir, Begin and Sadat in Israel
 
 
Katzir, wife, children and grandchildren
 
 
 
The IDF Science corps under Katzir
 
 
Yeshayahu Leibowitz and Ephraim Katzir
 
 
Prof. Katzir in the lab
 
 
Prof. Ephrain Katzir, 1916-2009
English

More Questions than Answers

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Dr. Jun Miyamoto. Choosing Judiasm and science
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At the beginning of 2006, Dr. Jun (Yona) Miyamoto immigrated to Israel with his aging cat, Sean. After spending several months learning Hebrew in Jerusalem, he moved to Rehovot through a special program for new immigrant scientists and began to work in the lab of Prof. Amos Breskin of the Particle Physics Department.
 
Miyamoto's story is one of an ongoing attempt to build bridges between things that often seem to be light years apart: culture, religion, science and identity. The 40-year-old Miyamoto grew up in a rural area in Tokushima, near Osaka. His parents were both teachers: His father taught English and his mother kindergarten. "As a child, I loved foreign languages and geography, and, of course, science. But religion was never discussed. Holidays were about tradition, and there is no institution of communal prayer in Japan. As I grew up, I became curious about religion. At 17, I left Japan for the U.S., which I still think of as my second home."
 
Miyamoto received his Ph.D. from the University of Michigan, where he worked on particle detectors. During his studies, he also managed to travel around the world. His M.Sc. is from the University of California at Berkeley, and this is where he first became interested in Judaism. "I met Yona, a religious Jew who was physically handicapped from birth, in the dorm cafeteria. We became good friends, and this eventually led to my becoming his helper, assisting him with things he couldn't do on his own. I was happy to help, and the two of us often engaged in intellectual and philosophical discussions. He took me to his mother's house near the Berkeley campus on the holidays and to the synagogue as well. I fell in love with the warmth of the Jewish community and with their sense of humor."
 
At first Miyamoto was interested in the people he met, but after a while he found himself drawn to the religion, as well. He read many books on Judaism and eventually underwent religious conversion in Canada in 2005. Today an Orthodox Jew, he has even learned to cook "Jewish" food, including gefilte fish, knaidelach, kugel and tzimmes. There have been challenges, as well – finding a place of worship where he feels comfortable, for instance, or submitting to the inspections of Orthodox matchmakers.
 
At the Institute, he participates in the development of novel radiation detectors. These so-called THGEM hole-multipliers, when coated with photosensitive materials, become highly sensitive light detectors. They are developed for measuring light emitted within large volumes of ultra-pure gas following rare interactions with certain cosmic particles – at this point theoretical – which are promising candidates for the mysterious dark matter that is thought to comprise 75% of our universe. To spot these particles, the detectors must be insensitive to cosmic and environmental background radiation; Miyamoto is investigating ways to create these conditions.
 
Miyamoto concedes that Judaism is not a religion for those seeking a simpler life or easy answers. "In general, there are more questions than answers, as well as added responsibility and obligations. As I get deeper into the world of particle physics, I want to find ways to integrate my faith with my profession." 
 
Prof. Amos Breskin's research is supported by the Helen and Martin Kimmel Center for Archaeological Science. Prof. Breskin is the incumbent of the Walter P. Reuther Chair of Research in Peaceful Uses of Atomic Energy.
 
 
 
 
 
Dr. Jun Miyamoto
English

Cancer Matters

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Prof. Moshe Oren and Yaara Ofir Rosenfeld. mechanisms of cancer growth
 
 

 

Israel Prize winner Prof. Moshe Oren: "We won't allow the tumor to escape the therapy"


Cocktails. That's the key word in the future fight against cancer, says Prof. Moshe Oren of the Weizmann Institute's Molecular Cell Biology Department, a pioneer of research into the molecular mechanisms of cancer. Advanced medicine will be customized on the basis of a patient's individual genetic profile. If a malignant disease is diagnosed, physicians should be able to prescribe effective treatments with a high likelihood of a cure. Oren, winner of the 2008 Israel Prize, believes these future cancer treatments will consist of a blend of several drugs, similar to the antiviral cocktails that currently keep AIDS at bay. "No single cancer therapy will probably work sufficiently well, and even if it does, the tumor might develop resistance to the drug," he says. "But if the patient receives drugs targeting two different mechanisms, the tumor is much less likely to 'escape' this onslaught."
 
The major advantage of personalized, molecular drugs is fewer and weaker side effects: These therapies will kill the tumor without killing the patient. But how will the drugs be tailored to each patient's needs? Says Oren: "The drug cocktail will target the dominant genetic defects in each person's cancer. Hopefully, we won't have to invent the cocktail each time from scratch but will identify groups of people that respond to certain drug combinations, based on their particular genetic makeup. The right patients should get the right drugs at the right time, as people with cancer often don't get a second chance."
 
A number of molecular therapies currently tested in clinical trials are based on Oren's research into p53, the tumor suppressor gene that is most frequently altered in human cancers. The p53 gene is known as the "guardian of the genome" because it puts the brakes on cancer when the cell's genome is damaged. When these "brakes" are not functioning properly, the road to cancer remains open. In 1983, together with collaborators, Oren was the first to isolate and clone p53, and in subsequent years, he made major discoveries about the way p53 works in normal and cancerous cells. Here he discusses the latest developments in p53 research, including his own most recent findings.
 

Therapies based on p53

 
"We now know that in the vast majority of cancerous tumors the tumor suppressor function of p53 is at least partially defective; but the nature of the defect varies greatly from one tumor to another. In about half of all cancers, the p53 gene itself is directly impaired. In such cases, the most appealing treatment strategy, now tested in clinical trials in China, is to deliver working p53 copies to cells by gene therapy. In other cases, the defect lies either in the genes controlling p53 or in the molecular machinery p53 uses to exert its effects – 'upstream' or 'downstream,' as the scientists say, from p53. In these instances, the therapy is aimed at correcting the defect in order to allow p53 to perform its cancer-blocking function.
 
"About ten years ago, we discovered one crucial 'upstream' mechanism: a genetic switch called Mdm2 that controls p53 activity. Mdm2's job is to make sure p53 is present in the cell in just the right amount by continuously destroying surplus p53 protein. If Mdm2 becomes overly active, it might destroy too much p53, depriving the cell of a vital tumor suppressor mechanism. Such excessive activity of Mdm2 is found in 10% to 20% of all cancers, particularly in sarcomas and in certain types of leukemia. Drugs that block Mdm2 so as to prevent an overzealous destruction of p53 are currently in Phase I clinical trials in the United States."
 

News from the battlefront

 
"In a recent study published in Molecular Cell and conducted in collaboration with researchers in the U.S., we discovered a previously unknown mechanism by which Mdm2 can dangerously decrease the amount of p53 in the cell. We found that Mdm2, in addition to binding directly to p53 and driving its destruction, can reduce p53 levels indirectly – by countering a protein called L26, which plays a pivotal role in p53 synthesis. In other words, Mdm2 can both inhibit the production of the p53 protein and accelerate the demise of the protein that has been produced.
 
"Before we can tell if this finding could lead to a new drug, scientists must determine whether the binding site between the two molecules, Mdm2 and L26, is structurally a good drug target. If it is, I could envision a drug cocktail that would target two separate mechanisms involving Mdm2 – the one we discovered more than ten years ago and the new, indirect one we discovered recently."
 

The origins of complexity

 
"Surely, nature didn't devise several control mechanisms for p53 synthesis just to frustrate cancer researchers. Its goal is to keep p53 levels low when all is well, but to raise them rapidly and efficiently when cancer-causing changes occur in the cell. It's difficult to achieve such a rise with a single mechanism."
 

The challenges ahead

 
"Most new-generation drugs for treating cancer are directed at signaling enzymes, which have been extensively studied. These enzymes include receptors that often are easily accessible on the surface of cells, particularly through the use of specific antibodies. In contrast, p53 operates in the cell nucleus, which is more difficult to reach and must be targeted with specially designed small molecules."
 
Prof. Moshe Oren's research is supported by the Robert Bosch Foundation.
 
 
 
Prof. Moshe Oren and Yaara Ofir Rosenfeld. Guarding the guardians
Life Sciences
English

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