Biting Truths

English

Sussman, Katzir, Fuchs, Fridkin, Harel, Balass, Scherf and Kashner. Snapshot

 

 

 

Count on the snake for the promise of hidden, enticing knowledge. The reptile has lured Weizmann Institute scientists into cracking one of its most precious secrets: how snake venom gains its deadly, irreversible grip on a victim. Several Institute teams took part in the series of studies that lasted more than a decade and unfolded like a scientific detective story, recently culminating in success.


What the scientists have accomplished is equivalent to reconstructing a murder act in minutest detail. Using knowledge obtained from different fields of research, they produced a precise three-dimensional snapshot of a major snake venom toxin in the act of blocking vital communication pathways in the body - a blockage that often causes death within hours.


The potential payoff is far-reaching. One obvious outcome is the prospect of a drug for treating snakebite, a largely neglected plague. About a million people worldwide are bitten by venomous snakes every year; most deaths - an estimated 40,000 annually - occur in developing countries, where antivenom, currently the only effective remedy, is in short supply or unaffordable by the local population. Antivenom is produced by isolating antibodies from the serum of horses immunized by certain venoms. By revealing how a major snake toxin works, Weizmann Institute scientists have opened the way to developing a synthetic drug that would trap the toxin molecules, preventing them from harming the snakebite victim.


The implications of the Weizmann research, however, go far beyond treating snakebite. The snake toxin hooks up with molecules in the body at a busy place - the very spot that serves as a gateway for signals responsible for nerve-muscle communication. All our voluntary muscle movements, from furrowing the brow to high jumping, are dependent on these signals, which are transmitted by messenger molecules such as acetylcholine, released by the nerves. In fact, certain types of venom paralyze the body by blocking acetylcholine receptor molecules on the muscle, thus interrupting nerve-muscle communication.


But apart from carrying messages to the muscle, acetylcholine is also one of the most important molecules transmitting signals between nerve cells in the brain. This explains why abnormalities in the binding between acetylcholine and its receptors are involved in a multitude of both muscle and nervous system disorders, from myasthenia gravis to schizophrenia to Alzheimer's and Parkinson's diseases. The structural understanding of acetylcholine receptor's binding site obtained in the Weizmann study may therefore facilitate the development of a wide variety of therapies.


Snake-inspired sleuthing


The scientific sleuthing began in the laboratory of Prof. Sara Fuchs of the Immunology Department, who, for nearly three decades, has worked on the structure of the acetylcholine receptor and on disorders involving this receptor. In the mid-1980s she identified a tiny region of the receptor - comprising a dozen amino acids out of a total of nearly 3,000 - that was capable of binding with a major snake toxin called alpha-bungarotoxin. Next Fuchs launched an investigation to resolve a long- standing riddle: why some animals - the snakes themselves and their archenemy, the mongoose - are immune to snake venom. Her studies revealed that in both snakes and mongooses the structure of the acetylcholine receptor differs slightly from that of other animals. The difference was observed in the same tiny region that had earlier been shown to bind with alpha-bungarotoxin; apparently this small structural deviation suffices to protect the animals by preventing venom from binding. The scientists hypothesized that they had zeroed in on the receptor's binding site, its 'holy of holies.' But how could they prove this?


In the early 1990s, Fuchs teamed up with Institute Prof. Ephraim Katzir. A world-famous biochemist and one of the founders of biological research at Weizmann, Katzir later served as President of Israel and then returned to the Institute to continue his research in biological recognition. Now 85, Katzir did not balk at embarking upon a new area of study. His team member Dr. Moshe Balass, together with Fuchs, searched through a huge 'library' of peptides (protein fragments) until they identified one peptide that had a specific interaction with alpha-bungarotoxin. The result was both surprising and rewarding: The peptide corresponded to the exact spot in the acetylcholine receptor that Fuchs had marked in earlier studies as the potential binding site.


To obtain more knowledge of the binding site, Fuchs, Katzir, and Balass formed yet another collaboration - with Prof. Jacob Anglister of the Structural Biology Department and Dr. Tali Scherf, now of the Institute's Chemical Services. These studies, using nuclearmagnetic resonance (NMR)spectroscopy, revealed crucialstructural aspects of the binding between the peptide and alpha-bungarotoxin.


Details of the deadly grip


The next breakthrough occurred when a team consisting of Katzir's postdoctoral fellow Dr. Roni Kasher, Balass, Fuchs, Scherf, and Prof. Mati Fridkin of the Organic Chemistry Department took advantage of the NMR data; using sophisticated modification methods they designed a new series of peptides with an exceptionally good fit to the snake toxin. Kasher then created crystals of the peptide and the toxin, needed for an X-ray analysis. The stage was now set for a precise structural analysis of the peptide-toxin complex. Scherf used NMR to probe the complex while Prof. Joel Sussman of the Structural Biology Department, author of several landmark papers involving acetylcholine, applied X-ray crystallography. What reinforced the findings was that the structures that emerged from the two different technologies were similar.


Still the evidence regarding the location of the binding site remained circumstantial because a crucial piece of the puzzle was missing: To obtain a full picture of the toxin in action the scientists needed crystals of the entire acetylcholine receptor, which, despite numerous attempts by laboratories around the world, has not yet been crystallized. Sussman managed to provide the next best thing: he contacted Dutch colleagues who had crystallized a protein that is virtually identical to the outer portion of the acetylcholine receptor - the portion that protrudes outside the cell membrane and harbors the binding site.


The scientists could now map the atomic structure of the snake toxin blocking the acetylcholine receptor. Using X-ray crystallography, Sussman and Dr. Michal Harel of the same department revealed that the three-pronged toxin molecule wraps around acetylcholine's binding area, inserting its middle 'finger' directly into the binding site gorge. This picture explains the exact way in which the venom blocks access to acetylcholine, preventing the nerve message from reaching the muscles. Little wonder that the venom's paralyzing grip on the victim is irreversible!


The new structural knowledge obtained in this research may prove a powerful tool in developing antivenom drugs as well as in the design of therapies for disorders involving the acetylcholine receptor. While its reputation may have been tarnished by its sneaky role in Adam and Eve's banishment from the Garden of Eden, this time around, the snake seems to have more than delivered on its promise to impart valuable knowledge.


Prof. Sara Fuchs holds the Professor Sir Ernst B. Chain Chair of Neuro-Immunology.

Prof. Ephraim Katchalsky-Katzir holds the Theodore R. Racoosin Chair of Biophysics

Prof. Mati Fridkin holds the Lester B. Pearson Chair of Protein Research

 
Prof. Joel Sussman, Prof. Ephraim Katzir, Prof. Sara Fuchs, Prof. Mati Fridkin. Top: Dr. Michal Harel, Dr. Moshe Balass, Dr. Tali Scherf, Dr. Roni Kasher
Life Sciences
English
  • AChE
  • Biological Chemistry
  • Ephraim Katzir
  • Immunology
  • Jacob Anglister
  • Joel Sussman
  • Mati Fridkin
  • Sara Fuchs
  • Structural Biology

It's a Perfect Protein Match

English
Dr. Gideon Schreiber. Improving affinity
 
 

 

Searching for a soul mate, new friends, or just fresh contacts? Turns out that proteins have similar "goals." However, shaking off their single status generally doesn't come easy.

Biochemist turned protein matchmaker Dr. Gideon Schreiber took their fate to heart. Working with doctoral student Tziki Seltzer and other colleagues at the Weizmann Institute's Biological Chemistry Department, they developed a computer algorithm that calculates the rate at which two proteins associate, using it to fashion proteins with increased affinity -- of a hundred times or more. Their achievement, appearing in Nature Structural Biology, holds much promise for the pharmaceutical and food industries, since protein complexes are fundamental to many life processes.

Protein affinity is defined by the rate at which two proteins associate with each other to form a complex, divided by the rate at which this complex dissociates. To improve affinity one can either intervene to reduce protein "break-up" statistics or, alternatively, increase protein association rates. Dr. Schreiber chose the latter.

Since association rates are influenced by the protein's (genetically determined) design, the scientists used this relationship as their guiding principle, developing an algorithm capable of determining the genetic changes necessary to boost association rates.

As it turns out, the "decision" whether to connect or not to connect is up to amino acids -- the protein's building blocks. "A protein's shape, properties, and biological role are determined by the nature and sequence of its amino acid ingredients," explains Schreiber. "For instance, the protein association rate is determined only by electrically charged amino acids (only four out of the twenty commonly occurring amino acids)." This is why the new algorithm operates by determining how to genetically change the charge of specific amino acids within a protein, so as to enhance its bonding capacity.

 

Candles, Flowers, and a Good Bottle of Wine

But it goes one step further. A unique feature of the algorithm is that the changes it calls for do not need to affect the protein binding region itself (which would risk affecting the protein's properties). Rather, the algorithm essentially suggests ways to create the perfect ambience to cement the match.


"When put into solution, proteins generally float around aimlessly, binding from time to time. Our evidence suggests that when proteins pass one another quite close to the conformation in which they could bind, the criterion that actually guides and directs the formation of the protein complex is the electrical charge surrounding the binding region, called an attraction field. In nature, this feature is particularly prevalent in proteins that need to perform very quickly, such as anti-clotting proteins or ribonuclease inhibitors. What the new algorithm does is suggest the genetic changes needed to improve the attraction field of diverse proteins, thus optimizing their binding conformation," says Schreiber.

Computer simulations are far more efficient in pinpointing potentially successful complexes than the conventional approach, which is based on creating a large pool of mutations and discovering the optimal complex through trial and error. Using the algorithm, the Weizmann Institute researchers increased the formation rate of a specific complex (B-lactamase protein and its inhibitor) by a factor of 250 and significantly enhanced its binding strength.

The new protein match-up system may lead to diverse medicinal applications based on increasing or inhibiting protein activity, as well as to new diagnostic procedures, including antibody detection.
 
Ilustration: Protein looking for a match

 

 

 

 
 
Dr. Gideon Schreiber.
Life Sciences
English
  • Algorithm
  • Biological Chemistry
  • Computer simulation
  • Genetic engineering
  • Gideon Schreiber
  • Protein affinity

Trimming Down the Medicine Cabinet

English
 
Prof. Yoram Shechter (bottom left), Prof. Matityahu Fridkin (bottom right) and team members
 

 

 

 

 

 

 

 

 

 

 
The next item to join the miniaturization trend may soon be the medicine cabinet. Weizmann scientists have found a way to prolong the effect of medication; instead of taking a medicine tablet, say, four times a day, you'll only need to gulp it down once.
 
For example, the method, developed by Prof. Matityahu Fridkin of the Organic Chemistry Department, Prof. Yoram Shechter of the Biological Chemistry Department and Dr. Eytan Gershonov, who worked with both departments, has reduced the number of insulin injections needed in diabetic rats to a fourth. Instead of requiring two injections a day to keep glucose levels at a normal level, once in two days was sufficient.
 
Normally, when medication is taken, its level in the blood surges -- sometimes up to one hundred times more than what is needed for effective action. These high levels often produce damaging side effects, but are necessary to keep the drug in the bloodstream long enough to do its job. Then, within minutes to several hours, the drug is cleared from the circulation and a new dose is needed.
 
For several decades, scientists have been trying to invent a way of releasing drugs into the blood in a more even manner while prolonging the time the medication actively circulates in the body. However, this goal was achieved for only a very limited number of drugs.
 
Fridkin and Shechter's new technique may affect how numerous categories of drugs, including antibiotics and cancer medications, are released into the body. They devised several kinds of molecular "corks," each with a different tendency to disintegrate in the bloodstream, and attached them to the medicine's molecules. According to the scientists, the corks prevent the medicine's active ingredients from seeping into the bloodstream in large quantities. Corks more prone to disintegration come off first, releasing the active medicine ingredients, while those less prone to disintegration hold out longer. Thus, the corks release relatively low but steady quantities of the drug into the patient's bloodstream over a longer period of time.
 
The cork is a small organic molecule. In a test tube study, the Weizmann Institute scientists found that it slowly disconnects from the drug under the temperature and pH conditions equivalent to those in human blood.
 
By altering the molecule's chemical features, the scientists created different versions of the molecular cork that can be disconnected at different rates, so that the speed of the drug's release into the circulation can be more precisely controlled.
 
Trimming Down the Medicine Cabinet
 
Two additional aspects of this technology could contribute to the drug's long-term action. First, drugs modified with the cork are less susceptible to breakdown by enzymes than their unmodified counterparts. Second, the scientists have evidence that their cork attaches to a protein in the bloodstream that traps and holds onto it. This "hold" may prevent the drug from being cleared from the body too quickly.
 
Currently, the Institute scientists are exploring an additional potential advantage of this technology. Test-tube experiments suggest that the cork may improve drug absorption by the intestines. If these findings are supported by further animal studies, the cork may be used to help change the chemical properties of injected drugs so as to convert them into oral medications.
 
A start-up company, Lapid Pharmaceuticals Ltd., has recently been created by Pamot Venture Capital Fund and Yeda Research and Development Co. Ltd., the Weizmann Institute's technology transfer arm, in order to develop this technology for commercial use.
If all goes as planned, medication takers may have a reason to open a bottle of champagne. With a corkscrew, of course.
 
Space & Physics
English
  • Biological Chemistry
  • Drug
  • Mati Fridkin
  • Organic Chemistry
  • Yeda
  • Yoram Shechter

The Sting

English

Targeting nerve cells

 

Caveat: Don't be taken in by size. That's the rather pointed message delivered courtesy of the cone snail. Though small, its venom has a deadly, zooming-in quality that makes these creatures especially noxious. Dr. Michael Fainzilber of the Biological Chemistry Department is part of the effort to turn these killers into healers.

"My uncle told me never to touch cone snails when I was a child, so I'd pick them up carefully and collect them," he recalls.

Fainzilber's childhood interests in Africa carried into adulthood in Israel, and into an important discovery: He has uncovered one of the cone snails' paralyzing, lethal proteins and followed its deadly sequence of destruction. These proteins are unique in their specificity. Specialists in pharmacology and biomedicine are taking note, as specificity is the name of their game.
 
Many of the Institute's scientists wend their way to Israel in an intriguing fashion; Fainzilber's story is especially captivating. Born in Tanzania, then a British colony to which Holocaust refugees were sent, he'd go swimming in the waters off its eastern coast in search of interesting shells.

Faintly conscious of a land called Israel, to which his father had been refused entry by the British after fleeing Europe, he did not feel like the son of outcasts. Tanzania, after all, was so rich in the natural treasures which feed a child's curiosity. "We had lions near our backyard," he says.

The world's troubles would soon have an effect on his life as well. Independence in Tanzania in 1961 led to a shift towards communism. One day in 1972, Fainzilber's parents told him that they were all going off on a "holiday." Their destination was Israel, by then independent for almost 25 years. Luckily for the 10­year­old Fainzilber, they settled in Haifa, the main port city of Israel ­ where he could keep up his snorkeling.

Since that time, one could say he's been "snorkeling his way" to the Weizmann Institute. When asked to name the oceans or seas in which he hasn't gone diving, Fainzilber is stumped. More than just a pastime, his diving has meshed with his scientific work, bringing him to the Weizmann Institute this past year.

With the help of his friends at the Free University of Amsterdam and UC San Francisco, Fainzilber has already discovered one paralyzing protein in the snail's venom and sequenced it. What this toxic protein does is latch on to a very specific site on the nerve cell of its prey, pulling open one of its channels. The channels, situated on the cell membrane, act as "doors" to the cell, letting particles in only at the turn of a "key." The key opening this particular channel is normally a specific combination of four neuropeptides.

This toxic protein dodges the channel's four-peptide "combination-lock" and opens the channel to streams of ion particles. The cell's innards become a free-for-all, the ion inflow unregulated. Since ion particles set off a signal instructing muscle contraction, the result of their unregulated flow is constant muscle contraction ­ in other words, paralysis.

The scientific importance of Fainzilber's discovery may lie in the special features of its target. "The channel targeted by the toxin is a pacemaker channel, meaning it regulates rhythmic processes," says Dr. Fainzilber. "The challenge now is to find similar toxins that could target other pacemaking channels, for example, in the heart. Then we may be able to engineer them to do something useful. One could call it an effort to turn swords into plowshares."
 

Stinging cone snails

Space & Physics
English
  • Biological Chemistry
  • Michael Fainzilber
  • Nerve cell

The Smell of Success

English

Profs. Meir Wilchek (left) and David Mirelman

Popular belief attributes to garlic a host of wondrous abilities, from fighting disease to keeping away vampires. Now Weizmann researchers have provided new evidence that this pungent-smelling plant really is good for us.

Raw garlic, it turns out, is an excellent, although smelly, natural broad-spectrum antimicrobial drug. And, among other beneficial effects, it may prevent cholesterol from clogging up the arteries.

Institute scientists were able to clarify how garlic works after developing a unique biotechnological procedure for producing large quantities of pure allicin, the main biologically active component of garlic and the one responsible for its smell.

Profs. David Mirelman and Meir Wilchek of the Institute?s Biological Chemistry Department headed the project, working with colleagues Drs. Serge Ankri, Talia Miron and Aharon Rabinkov, and with Prof. Lev Weiner and Dr. Leonid Konstantinovski of the Organic Chemistry Department.

The scientists discovered that allicin has the power to render dysentery-causing amoebas harmless. That's because allicin blocks two groups of enzymes without which amoebas cannot survive or invade and damage tissues. These types of enzymes are also present in a wide variety of infectious organisms, such as bacteria, fungi and viruses. Thus, by blocking the enzymes, allicin can ward off a wide range of infections. Allicin's role in fighting infection may be particularly valuable in light of the growing bacterial resistance to antibiotics.

The researchers found that allicin produces its blocking effect by reacting with molecules known as sulfhydryl groups. Sulfhydryl groups are among the essential elements of the enzymes found in infectious organisms, but they are also crucial components of other enzymes, some of which participate in the synthesis of cholesterol. Thus, by reacting with and modifying the sulfhydryl groups, allicin not only disables infectious organisms but also may help prevent the clogging of arteries.

Moreover, the researchers provided evidence that allicin can act as an antioxidant, gobbling up harmful oxygen molecules believed to contribute to atherosclerosis, tumor growth, aging and other processes.

Allicin, which in nature protects the garlic plant from soil parasites and fungi, is created when garlic cloves are crushed. Crushing causes two components of garlic, allicin and the enzyme alliinase, to interact. The biotechnological method developed at the Weizmann Institute makes it possible to produce semi-synthetic allicin.

A patent application for the production of allicin has been submitted by Yeda Research and Development Co. Ltd., the Institute's technology transfer arm, and several companies have already expressed interest in scaling up the process for clinical testing and commercial use.

Prof. Mirelman holds the Besen-Brender Chair of Microbiology and Parasitology, and Prof. Wilchek, the Marc R. Gutwirth Chair of Molecular Biology. This research was funded in part by the Center for Molecular Biology of Tropical Diseases at the Weizmann Institute; the Avicenne Program of the European Union; the Center for the Absorption of Scientists, Israel's Ministry of Absorption; and France's Foreign Ministry. Research facilities: Mrs. Ellen Epstein, Haifa, Israel; Mr. and Mrs. Sanford Diller, Los Angeles, California.
Space & Physics
English
  • Antibiotics
  • Biological Chemistry
  • David Mirelman
  • Garlic
  • Meir Wilchek
  • Yeda

A Molecular Radar

English
Prof. Ben-Zion Shilo, Limor Gabay, and Dr. Rony Seger. Message delivery

Modern technology allows us to track movement invisible to the naked eye, from ships sailing beyond the horizon to orbiting satellites in outer space. Scientists at the Weizmann Institute have now introduced tracking to the frontiers of inner space as well. They have developed a molecular "radar" that, for the first time, makes it possible to track signaling enzymes inside a cell in real time.

 

Using this molecular "radar," the scientists have mapped the exact progress of an intercellular messenger that plays a key role in embryonic development.

The achievement, featured recently on the cover of Science, is expected to prove valuable in gaining a better understanding of how signals are transferred inside a cell and how the signaling process goes awry in diseases such as cancer. It could also help resolve the mystery of how cells in an embryo manage to form the different types of tissues and organs of a human or animal body.

"Previously, in studying message transmission inside the cells of a developing organism, we scientists were rather like people at an airport watching the planes take off and land," says research team leader Prof. Ben-Zion Shilo, head of the Institute's Molecular Genetics Department.

"We could make some intelligent inferences about where the planes were going or where they had come from, but we couldn't see the course a plane was following.

"Our new method gives us an ability equivalent to that of an air traffic controller, who looks at the dots on the radar screen and can thus follow the movements of each plane step by step," Shilo says. "Suddenly we can look at processes in a cell or an embryo as they are happening and we don't have to infer things from the consequences any more."

Shilo conducted the study with Dr. Rony Seger of the Biological Regulation Department and with doctoral student Limor Gabay of the Molecular Genetics Department.

The starting point for the study was the knowledge that many messages inside cells are passed on by means of phosphate atoms.

When a molecular messenger, such as a hormone, attaches itself to a receptor on the cell membrane, it sets off a chain reaction inside the cell in which one molecule activates the next, through the addition of phosphate atoms, a process known as phosphorylation.

To track the activated, phosphate-containing molecules, the team developed antibodies that react only with molecules phosphorylated in a particular fashion. Since these antibodies can be easily traced, the system allowed the scientists actually to observe phosphorylation --  the pathway of signal transmission -- in real time.

Shilo and his team worked with Drosophila fruit flies. These insects are used commonly in scientific research because they share many genetic and molecular characteristics with higher animals, develop rapidly, and are easy to study. The researchers focused on a hormone-like messenger called epidermal growth factor (EGF), which becomes active during embryonic development and ensures the formation of a proper body pattern.

Using the new method, they followed the signal transmitted by EGF from the point at which EGF attaches to its receptor on the cell membrane up to the time it delivers the message to the genes in the cell nucleus. They were able to see precisely when and where the signal is passed on within individual cells, and also to observe which cells within an embryo are affected by EGF at different stages of embryonic development.
 

Drosophila Fruit Fly. Easy to study

"We can trace signals in several cells simultaneously and chart an atlas of signal transmission for the entire embryo," says Shilo.

The new molecular "radar" is also a valuable tool for studying phosphorylation patterns set off by other receptors, and for investigating phosphorylation in other organisms, including humans. It can shed light on both normal development and abnormal tissue growth, such as in cancer.

"Clearly, we can use this method to track the phosphorylation pattern in these diseases, and it could be a useful diagnostic tool for finding where things are going wrong" says Shilo. "And if you can see where things are going wrong you can set about finding specific ways to stop them."

Dr. Seger holds the Samuel and Isabelle Friedman Career Development Chair. This research was funded in part by the Dr. Josef Cohn Minerva Center for Biomembrane Research at the Weizmann Institute; the Tobacco Research Council of the United States; the U.S.-Israel Binational Science Foundation; the U.K.-Israel Science and Technology Research Fund; the Minerva Foundation, Germany; the Lynne and William Frankel Fund for the Diagnosis and Treatment of Ovarian and Breast Cancer, Philadelphia, Pennsylvania. Antibodies for this research were developed in collaboration with Sigma Israel Chemicals Ltd. Research facilities: The Ner Trust, Inc., Zurich, Switzerland.
 
Space & Physics
English
  • Ben-Zion Shilo
  • Biological Regulation
  • Hormone
  • Molecular Genetics
  • Rony Seger
  • Signaling

High Salt, High Hopes, High Tech

English

From the Land of the Rising Sun to the Land of Abundant Sunshine. One thousand Nikken Sohonsha salespersons who market a beta-caroten-rich health food supplement produced with the help of Weizmann science visited the campus recently

Nikken Sohonsha salespeple at the Institute

 

Dunaliella bardawil, a single-celled alga so resistant to salt and sunlight that it can even survive in the hostile environment of the Dead Sea, is turning out to be a very versatile little creature.


It was Weizmann Institute scientists -- the late Prof. Mordhay Avron and his co-worker Dr. Ami Ben-Amotz -- who studied Dunaliella and learned to exploit the hardy alga's ability to produce vast quantities of beta-carotene, a natural pigment and source of Vitamin A. The Weizmann findings became the basis of a thriving export industry. Nature Beta Technologies, an algae-growing enterprise in Eilat owned by the Japanese company Nikken Sohonsha, produces beta-carotene-rich Dunaliella powder and other products that are sold as health food in Japan. And now two research teams headed by Profs. Ada Zamir and Uri Pick of the Biochemistry Department are exploring methods to boost and expand the alga's productivity in order to further increase its commercial value.

But beta-carotene is just one of the assets of this lowly plant. According to the scientists, Dunaliella's unique survival strategies could make this alga a rich source of other high-value biochemical items. Furthermore, they believe that Dunaliella has the potential to become a vehicle for creating "smart" genetically engineered substances for biotechnology industries. Because its high-salt environment is nearly sterile, mass production of the alga and its potential products holds little risk of contamination. Once the method is perfected, Dunaliella could serve as an economical natural "factory" for an unlimited number of genetically engineered products, including vaccines, drugs and hormones.

As a first step in mining the alga for useful biochemicals, the Weizmann researchers have isolated an enzyme and a transport protein in Dunaliella that are capable of carrying out a variety of biochemical processes under high salt and temperature conditions.

The alga research is being done within the framework of the Magnet Consortium, a program of Israel's Industry and Trade Ministry aimed at building partnerships between Israel's scientific research institutes and high-tech industries.

The Magnet Algae Consortium is made up of the Weizmann Institute of Science and Nature Beta Technologies (the Eilat-based company) collaborating on Dunaliella, and Israel's Oceanographic and Limnological Research Institute, working together with a kibbutz and a chemical firm on a related alga project.

"We are all investigating basic issues regarding the biology of algae," says Prof. Zamir. "But belonging to the Consortium has made the scientists more aware of the practical economic implications of our work, so that what we do has two aspects -- basic and applied."
Space & Physics
English
  • Ada Zamir
  • Alga
  • Biochemistry
  • Dead Sea
  • Mordhay Avron
  • Uri Pick

How the Mongoose Beats the Snake

English
The mongoose, as anyone who has read Rudyard Kipling's Jungle Book knows, has but one purpose in life: "to fight and eat snakes." Now a team of Weizmann Institute researchers, led by Prof. Sara Fuchs of the Immunology Department, has revealed how this small mammal manages to survive the effects of deadly snake venom.

When a poisonous snake bites, venom attaches itself to a protein message receiver on the victim's muscle cells, blocking the normal flow of signals sent from the central nervous system to the cell, thus paralyzing and ultimately killing the victim.

The Institute team has found that in mongooses -- and in snakes themselves -- the structure of the receiver, the acetylcholine receptor, is slightly different from that in other animals. The difference is small -- only four out of several hundred amino acids that make up the receptor differ -- but it is enough to prevent venom from attaching itself to the cells. So mongooses like Kipling's Rikki-tikki-tavi, and snakes themselves, are protected from otherwise deadly snake attacks.

Fuchs has spent more than two decades studying the acetylcholine receptor, a protein that plays a key role in muscle function and is also involved in the autoimmune neuromuscular disorder myasthenia gravis. Part of the research was done in collaboration with Tel Aviv University's Zoology Department .
Space & Physics
English
  • AChE
  • Immunology
  • Sara Fuchs

DNA "Repair Enzymes" Tricked into Producing Mutations

English

 

Prof. Zvi Livneh and Orna Cohen-Fix. Alternative mutation pathway
 

Vital "repair enzymes" responsible for preventing genetic mutations are at times hoodwinked into causing such mutations themselves, according to a recently published Institute study. It is known that environmental stress factors such as ultraviolet light or certain chemicals may create lesions on DNA strands, preventing the DNA molecule from issuing clear instructions on how to form an identical replica of itself. Were it not for the "rescue" operations of special "repair enzymes" -- proteins that search for lesions, cut them away and replace them with healthy DNA material -- mutations would be formed in uncontrollable fashion. However, Prof. Zvi Livneh and doctoral student Orna Cohen-Fix of the Department of Biochemistry have now found that these same enzymes can be duped into producing the very mutations they are designed to avert.


"Our hypothesis," says Prof. Livneh, "is that this occurs when two different lesions face one another on complementary DNA strands." The restoration procedure starts out normally, with the repair enzyme excising one of the lesions. "Then however," says Livneh, "the enzyme encounters an unexpected situation. The reserve store of information on the opposite strand, which it uses in order to fill in the gap, turns out to be faulty as well. A point of no return has been reached in the process, and the enzymatic machinery is left with no choice other than to proceed with the repair operation and to duplicate the defective material -- thereby producing a mutation."

This newly discovered process appears to be an "alternative" mutation pathway. In the more commonly recognized mechanisms, ordinarily dormant proteins called bypass factors help the DNA copying machinery to progress through lesions, thus generating permanent mutations in the cell's genetic material.

Livneh and Cohen-Fix used an original model system in which ultraviolet (UV) light-induced genetic changes are produced in test tubes by a protein extract from the bacterium Escherichia coli. The planned adaptation of this model to UV-exposed mammalian cells will allow the investigation of such dual pathways in mammalian systems, including those of humans.

Support for this work has been provided by the U.S.-Israel Binational Science Foundation and the Minerva Foundation, Munich, Germany.

Schematic diagram of lesion entering DNA duplicating machinery

 

Space & Physics
English
  • Biochemistry
  • DNA damage and repair›DNA repair
  • Mutation
  • Zvi Livneh

Biological Sensors Devised by Institute Scientists

English

Dr. Itzhak Yuli. Detecting drugs or explosives

 

A novel design for highly sensitive biosensors -- microelectronic devices that take advantage of biological detection and amplification mechanisms -- has been developed by Prof. Carlos Gitler and Dr. Itzhak Yuli of the Institute's Department of Membrane Research and Biophysics. Such biosensors may some day be used instead of animals to detect drugs and explosives, or to test pharmaceuticals and cosmetics. They may also be integrated into portable on-line monitors to greatly improve the sensitivity of standard chemical analysis performed in medical diagnostics, and eventually may be inserted into the human body to continuously monitor minute concentrations of chemicals relevant to various diseases.


Biological sensory systems are known to be nature's most efficient and highly selective detection devices. The environmental signals that living organisms detect through vision, smell or taste, and the internal signs involved in nerve triggering or hormonal stimuli, all produce changes in chemical states. Some of these chemical modulations activate a variety of ion channels -- proteins that by opening up create pathways for the flow of electrically charged elements through otherwise highly impermeable cell membranes.

The new biosensor design is based on an artificial biological membrane containing synthetic varieties of such ion channels, sophisticatedly attached to a gold electrode. These channels open up in response to specific chemical signals, causing modifications in the electrical conductivity of the membrane, which can be easily recorded.

The new bionic device will use a liquid crystalline phospholipid membrane that is indirectly attached to the gold electrode by "spacer arms" of detergent-like molecules. One end of these rod-like molecules blends naturally into the membrane, while the other end is modified so as to acquire a high affinity for gold. This design endows the membrane with both mechanical stability and structural flexibility, and minimizes the need to utilize an ultrasmooth electrode surface.

Sensing elements of two different types are under study. One of them involves synthetic polypeptides resembling melittin, a toxin in bee venom which spontaneously penetrates into cell membranes to form active ion channels. A second system uses genetically engineered proteins similar to natural ion channels that open upon recognizing a given substance.

Title to the patent on this biosensor design is held by Yeda Research & Development Co. Ltd., which promotes the commercial exploitation of know-how originating in the Weizmann Institute.

Prof. Gitler holds the E. Stanley Enlund Chair in Membrane Research.
 

Artificial membrane and ion channel

 
 
Space & Physics
English
  • Carlos Gitler
  • Membrane
  • Membrane Research and Biophysics
  • Sensor
  • Yeda

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