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Science Feature Articles</p>

Tending the Brain’s Garden

English
 
Dr. Oren Schuldiner. Remodeling in the developing brain
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The developing brain resembles a well-tended garden. Budding neurons sprout bushy extensions; but with time, unneeded extensions are “pruned,” as if by an invisible gardener. Entire segments are eliminated and connections between neurons are erased. Many of the neurons then grow new extensions, which wire up the adult brain with amazing precision.
 
This fascinating “garden design,” essential for sculpting the mature brain and nervous system, is being investigated in the lab of Dr. Oren Schuldiner, who recently joined the Weizmann faculty. Schuldiner seeks to reveal the molecular mechanisms that govern neuronal remodeling: What commands instruct segments of neuronal extensions (axons) to become fragmented and disappear? How do the axons know exactly at which spot to begin disintegrating? How does the axon begin to regrow? And what roles do various brain cells play in these remodeling processes?
 
Though it seems wasteful to wire up a developing brain by pruning, the seemingly excessive axonal growth in early development probably serves a purpose – one that scientists have yet to discover. It might, for instance, be simply easier to generate exuberant growth and later refine the brain circuits by trimming branches here and there, rather than immediately generating the correct connectivity. Whatever the reason, axonal pruning is obviously an evolutionary success story: It exists in living beings from worms to mammals, most certainly including humans.
 
Schuldiner was attracted to research into axonal pruning by the novelty of this important and challenging field. In his new lab in the Institute’s Molecular Cell Biology Department, he investigates this process in fruit flies, which can help clarify brain remodeling in humans. Fruit flies have long been considered an excellent model for genetic studies as they are small, cheap and reach maturity within 10 days. And, since each fly’s life cycle involves major transformations, from a larva to an adult fly, its brain undergoes massive pruning and remodeling.
 
During his postdoctoral studies at Stanford University, Schuldiner designed an approach that dramatically speeds up the screening of fruit fly genes. In such screening, scientists reveal the function of a gene by creating a mutation and observing its consequences; they then map the location of the mutated gene in the genome. To optimize this process, Schuldiner designed a technique for producing just the kinds of mutations that can be examined by MARCM, the pioneering method for viewing individually mutated neurons in the fruit fly brain that was developed by his postdoctoral supervisor Prof. Liqun Luo. As a result, the time it takes to map a fruit fly gene has been shortened from at least a year to just two days. Schuldiner and colleagues used the approach to create some 2,500 types of fruit fly, each with a unique mutated gene. These mutations, covering about 20% of the fly’s genome, provide researchers worldwide with a valuable resource for investigating individual fly genes.
 
With the help of this powerful method, Schuldiner identified a dozen genes involved in axonal pruning – about twice the number of all previously known pruning genes. At the Weizmann Institute, he is studying the function of these genes and searching for additional molecules and mechanisms that control the remodeling of the nervous system during development. Employing sophisticated genetic techniques and confocal microscopy, he is able to visualize single nerve cells within a whole brain while creating specific mutations in individual neurons.
 
One of the genes Schuldiner discovered serves as the first known molecular switch that triggers the regrowth of axons after pruning. He intends to find out whether this gene also triggers regrowth after nerve injury and whether it can be manipulated to help induce such regrowth, with a view to potential future therapies.
 
Because the fragmentation of axons after injury and in certain pathological conditions –
including Alzheimer’s disease and certain other neurodegenerative disorders – is similar to the fragmentation that occurs during developmental axon pruning, Schuldiner’s research on the developing fruit fly brain
could provide valuable new insights into nerve injury and various diseases of the nervous system.
 
 
Axon pruning in normal fuit fly brain
 
Unpruned axons in mutant fruit fly brain
 
 
 
 
 
 
 
 

From Sinai to Rehovot


Born in Tel Aviv, Israel, Dr. Oren Schuldiner conducted his undergraduate and graduate studies at the Hebrew University of Jerusalem. After earning a Ph.D. in genetics in 2002, he performed postgraduate research at Stanford University for five years. He joined the Weizmann faculty as a senior scientist in 2008. Schuldiner is married to Maya, a senior scientist in Weizmann’s Molecular Genetics Department, and has two sons: Daniel, seven, and Noam, four. While a student, he worked as a tour guide in Sinai and later wrote and edited the life science column in the Hebrew-language popular science monthly Galileo.
He enjoys hiking, mostly in the desert, as well as scuba diving, photographing people and scenery, and listening to jazz.
 

Dr. Oren Schuldiner’s research is supported by the Women’s Health Research Center funded by the Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research, the Harry and Jeanette Weinberg Women’s Health Research Endowment and the Oprah Winfrey Biomedical Research Fund; the Adelis Foundation; and the estate of Lela London.

 
 
 
 
Dr. Oren Schuldiner. Early pruning for proper growth
Life Sciences
English
  • Alzheimer's
  • Axon
  • Molecular Cell Biology
  • Mutation
  • Neural pathway
  • Oren Schuldiner

A Star’s Life

English

Dr. Avishay Gal-Yam. First view

 

S
 
In the first observation of its kind, scientists at the Weizmann Institute of Science and San Diego State University succeeded in following the evolution of a star the size of 50 suns. As they watched, it exploded and then vanished from view to become a large black hole.
 
A star’s end is predetermined from birth by its size and by the “power plant” that keeps it shining during its lifetime. Stars are fueled by hydrogen nuclei fusing together into helium in the intense heat and pressure of their inner core. When stars like our sun use up all their hydrogen fuel, they burn out relatively quietly in a puff of expansion. But a star that’s eight or more times larger than our sun makes a much more dramatic exit. Nuclear fusion continues after the hydrogen is exhausted, producing heavier elements in the star’s different layers. When this process progresses to the point that the core of the star has turned to iron, another phenomenon takes over: The enormous heat and pressure in the star’s center cause the iron nuclei to split apart into their component protons and neutrons, and at some point the star’s core collapses inward, firing the rest of the star’s material rapidly out into space in an explosion known as a supernova.
 
A supernova releases more energy in a few days than our sun will release over its entire lifetime. While a supernova’s outer layers are lighting up the universe with dazzling fireworks, the star’s core is collapsing further and further inward. The gravity created in this collapse becomes so strong that the protons and electrons are squeezed together to form neutrons, and the star’s core is reduced from a sphere 10,000 kilometers around to one with a mere 10-kilometer circumference. But if the exploding star is 20 times or more the mass of our sun, its gravitational pull becomes stronger still: Even light waves are held in place. Such a star – a black hole – is, to all intents and purposes, invisible.
 
Supernovae have been observed with the naked eye since antiquity, and many more have been observed in recent years through ground and space telescopes and via research satellites. Yet until now, none of the exploding stars that scientists have managed to measure had exceeded a mass of 20 suns.
 
Dr. Avishay Gal-Yam of the Weizmann Institute’s Faculty of Physics and Prof. Douglas Leonard of San Diego State University were recently the first to directly observe the process by which a really huge star becomes a black hole. They were looking at a certain region in space using the Keck Telescope on Mauna Kea in Hawaii and the Hubble Space Telescope. The scientists were able to locate a star on the verge of exploding and to measure its mass before the blast. They found that this star’s size was equal to 50 – 100 suns. Continued observation revealed that only a small part of the star’s mass was flung off in the explosion. Most of the material, says Gal-Yam, was drawn into the collapsing core as its gravitational pull increased. Indeed, in subsequent telescope images of that section of the sky, the star seemed to have disappeared. It has now likely become a black hole so dense that even light can’t escape the pull of its immense gravity.
 

Dr. Avishay Gal-Yam’s research is supported by the Nella and Leon Benoziyo Center for Astrophysics; the Peter and Patricia Gruber Award; the Legacy Heritage Fund Program of the Israel Science Foundation; the William Z. and Eda Bess Novick Young Scientist Fund; and Miel de Botton Aynsley, UK.

 
Dr. Avishay Gal-Yam. Intense gravity
Space & Physics
English
  • Astrophysics
  • Avishay Gal-Yam
  • Supernova

In the Eye of the Vortex

English

Prof. Eli Zeldov probes superconductor physics

Visitors to the lab of Prof. Eli Zeldov in the Weizmann Institute’s Condensed Matter Physics Department are often treated to the sight of a magnet floating in midair. The trick? Beneath the magnet, a superconductor – a chunk of copper oxide-laced ceramic, cooled to -196°C (-321°F) repels its magnetic field. This feat convinces most visitors that superconductors – materials able to conduct electricity with zero resistance – are super cool.

 
But it’s not nifty party tricks that make superconductivity such a buzz word these days. The complex interaction between superconducting materials and magnetic fields drives not only the levitation of Zeldov’s modest magnet but also entire trains. From super-fast trains that glide nearly frictionlessly over magnetic tracks at over 600 kilometers per hour to electronic filters associated with cell phone towers to MRI machines, superconductor applications are surprisingly diverse. “Although a lot is known about superconducting materials, there are still many gaps in our understanding as to why and how these substances superconduct in the first place,” says Zeldov.
 
What scientists do know about superconductors is that magnetic fields can entirely erase the superconductive properties of a material. Superconducting materials, however, often “defend” themselves by repelling external magnetic fields they are exposed to – a phenomenon known as the Meissner effect.
 
Yet magnetic fields are able to partially penetrate certain types of superconductors; the penetrating magnetic field breaks up into small “islands,” which take the form of tubular whirlpools called vortices. When this happens, superconductivity is maintained outside the vortices, even as it’s destroyed within them. Such vortices pose a problem: They move around through the material in the presence of an electric current and this movement results in resistance. Vortices can thus render a superconductor little better than conventional copper wiring. To impede vortex movement, scientists have devised methods for pinning them to carefully planned defects within the superconducting material, allowing the current to flow more efficiently.
 
Since the majority of superconductor applications involve magnetic fields, an in-depth understanding of vortex physics has far-reaching practical implications. A team of scientists at Stanford University, including Weizmann alumnus Dr. Ophir Auslaender, who took a leading role in the research, and Zeldov developed an innovative tool that has allowed scientists to get closer to vortices than ever before. In a paper published in Nature Physics, they provided an updated analysis of the microscopic defects at the root of vortex pinning, as well as of vortex structure and dynamics.
 
The novel method employs a magnetic force microscope; the scientists use its miniscule magnetized tip not only to measure the physical properties of individual vortices, but also to manually move the vortices around in the superconducting material. Thus, the Stanford and Weizmann scientists demonstrated how manipulating a single vortex can be used to probe both the interactions of vortices and the structure of pinning defects within the material. Understanding vortex interactions on such a small scale is invaluable for building the “big picture” of superconductor behavior needed for the effective application of superconductor technology.
 
The microscope study yielded some surprising results regarding one of the most studied superconducting materials to date – yttrium barium copper oxide (YBCO). This material is among the so-called “high-temperature” superconductors, which lose their resistance at temperatures that, while still inhumanly low, are much higher than the near-absolute-zero temperatures needed for most superconductors. This makes them useful candidates for many applications. Probing single vortices showed that the internal structure of YBCO is much more varied than previously thought, and there were new revelations about vortex dynamics, as well. For instance, by wiggling a vortex while dragging it, the team found that it can be pulled much farther than usual – by an order of magnitude. This finding may help to explain vortex behavior in the presence of alternating currents.
 
This method has an advantage over most local probing techniques, which only give information about the immediate surface of the superconductor as opposed to what lies beneath. The results of this research have given scientists quite a bit of material for further investigation and modeling is underway to help interpret them. Yet despite the advantages of the technology, this method of measurement is intrusive, as the magnetic tip interacts with vortices in the sample. Zeldov’s team at Weizmann is currently developing a new non-intrusive method for measuring individual vortices – one that will hopefully “levitate” an understanding of superconductivity to a higher plane.

Prof. Eli Zeldov is the incumbent of the David and Inez Myers Professorial Chair.
 
Prof. Eli Zeldov. Pinning down superconductivity
Space & Physics
English
  • Condensed Matter Physics
  • Eli Zeldov
  • Magnetic field
  • Superconductor

The Organ Underground

English

R’ada Massarwa, Ben-Zion Shilo, Eyal Schejter. transporting substances in the cell

 

 
The London Tube is the city’s lifeline, transporting people to every corner and back. Similarly, the body relies on networks of tubes – tubular organs such as the gut, windpipe and glands – to transport such bodily substances as solutes, hormones, nutrients, oxygen and waste products.
 
The inner lining of the tubular organ is composed of a layer of specialized epithelial, or “outer,” cells, which, among other things, control the secretion of useful substances into the organ’s “tunnel.” To enter the tunnel, these substances must first make their way to the exposed edge of the epithelial cells. Special proteins within the cells lead the substances in the right direction, but how they do this is not exactly clear.
 
An epithelial cell’s tunnel-facing edge is always rich in “cables” made from a common protein called filamentous actin. “Who” makes these actin cables? How do they become localized only in the cell’s tunnel-facing edge? What is their function there? New research recently published in Developmental Cell by Prof. Ben-Zion Shilo, together with (then) research student Dr. R’ada Massarwa and Dr. Eyal Schejter of the Weizmann Institute’s Molecular Genetics Department, has provided, for the first time, possible answers to these questions
.
Working with fruit fly embryos, the team discovered that a protein called Dia was responsible for the specialized actin structures. When the scientists removed the gene for Dia production, they found signs of filament production along other parts of the cell, but no cable structures were being formed along its tunnel-facing edge. Further experiments revealed that in order for Dia to carry out its function, it first has to be activated by other types of proteins. These Dia-activating proteins are bound to the tunnel-facing side of the epithelial cell, thus ensuring the cables’ polarized distribution.
 
How exactly are the actin cables used? The scientists noted that in cells where cables weren’t produced, no substances were secreted into the organ’s tunnel. In other words, the actin cables seem to be the “route” the substances need to travel to arrive at the tunnel. The team discovered that the substances are “shuttled” on a type of “cable car” – a motor protein called myosin V – which transports them along the actin cable and drops them off at the tunnel entrance, from which they eventually get secreted.
 
“Our research shows that this mechanism for secretion in the fruit fly embryo is employed in different tubular organs, regardless of their size and function,” said Shilo. “For our next study, we plan to check whether the same mechanism is found in mammalian species, including humans. We hope that these insights will help us gain a better understanding of the mechanisms involved in secretion by tubular organs and, on a practical level, to improve doctors’ ability to deal with pathological situations that are caused by a failure of the secretion process.”
 
Prof. Ben-Zion Shilo’s research is supported by the Jeanne and Joseph Nissim Foundation for Life Sciences Research; the Mary Ralph Designated Philanthropic Fund; the Carolito Stiftung; La Fondation Raphael et Regina Levy; and the estate of Georg Galai. Prof. Shilo is the incumbent of the Hilda and Cecil Lewis Professorial Chair of Molecular Genetics.
(l-r) Dr. R’ada Massarwa, Prof. Ben-Zion Shilo and Dr. Eyal Schejter. On the secreting edge
Life Sciences
English
  • Ben-Zion Shilo
  • Fruit fly
  • Hormone
  • Molecular Genetics

Combining Minds

English
 

Dr. Elad Schneidman. A neuron collective

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

The scope of the brain’s activities presents scientists with a seemingly impossible challenge: Each of its 100 billion nerve cells – neurons – is in contact with about 10,000 others. They communicate through a series of electrical signals that get translated, at the synapses between them, to chemical signals. To interpret these “conversations,” we would need a sort of “bar code scanner” that could read the electrical signal patterns. But even for a relatively small group of cells – just 100 – the number of possible combinations of signals is 1030 (that’s one followed by 30 zeroes) – more than all the stars in the universe.

 
Clearly, mapping the brain neuron by neuron is an impossible feat; thus, many scientists choose to look at the small picture – interactions between small groups of neurons. But Dr. Elad Schneidman of the Institute’s Neurobiology Department adopts the lessons from small networks and develops new methods for combining them to decipher the workings of larger ones. He takes as his starting point groups of tens or hundreds of interconnected neurons, working upward from the observed relations between pairs and triplets of cells. “The most interesting activities involve hundreds or thousands of neurons. With today’s technology, we can investigate groups of 100 to 200 – enough to allow us to explore the fundamental design principles of brain networks,” he says. And his results are providing insight that couldn’t be obtained with individual-neuron methods. In his postdoctoral research, for instance, he showed that, even though the typical correlation between pairs of neurons is weak, the combined effect of these correlations in the group is strong. “It’s like peer pressure: One opinion doesn’t carry much sway, but the joint effect of many weak signals together can control the group as a whole.”
 
Using advanced computational tools borrowed from computer science and physics, Schneidman analyzes brain networks, breaking them down into their components and looking for patterns that can clarify the rules and regulations of collective behavior for large groups of nerve cells. For example, in a series of experiments conducted with Dr. Ronen Segev of Ben-Gurion University of the Negev, the electrical responses of a network of nerve cells in the retina of a salamander were recorded. The scientists showed long movie clips of the salamander’s natural environment to a group of 100 of these cells and measured their reaction, obtaining a bar code readout of patterns of electrical signals. After uncovering some of the basic rules of population activity, they then demonstrated that this allows for direct “reading” of the neuron code: Schneidman and his collaborators reconstructed the instantaneous gray level of a small part of the simple movie directly from the activity patterns of the neurons – a feat that is unattainable with single-cell methods.
 
The collective-as-a-complex-sum-of-its-parts approach may help to explain a puzzling phenomenon: that of the brain’s ability to deal with its own internal “noise.” Not only are single nerve cells notoriously inconsistent in their reactions to the same stimulus, but communication between cells is surprisingly unreliable, as well.
 
Schneidman believes that nature didn’t make the effort to create precise, noise-free nerve cells because getting them to act as a group is a “cheaper,” more efficient solution, and one that has other benefits: Such redundant activity, in addition to neutralizing noise, creates a sort of “backup” that keeps the activity going even when individual brain cells die. Furthermore, such noise may facilitate the use of trial-and-error tactics for learning.
 

The principles Schneidman is uncovering for the group activities of nerve cells may be valid for other systems. “These mathematical rules and models cross the borders between scientific fields,” he says. “Different physical and biological phenomena – from the collective actions of atoms in a magnetic field to cooperative food searching strategies of groups of animals – share similar organizing principles.” For example, he is working on mathematical models that elucidate the group behavior of shoals of fish seeking food or flies zeroing in on a food source. These models, he hopes, may provide insight into more complex group behavior: how individuals influence each other, the role of “free will” within the group and its limits, group learning, how groups deal with communal crises and more. Schneidman hopes that uncovering principles of group behavior will help shed light on little-understood aspects of social conduct in many kinds of creatures, including those that may possibly be the hardest to pin down – human beings.

 

Dr. Elad Schneidman’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Clore Center for Biological Physics; the Carl and Micaela Einhorn-Dominic Brain Research Institute; the Eisenberg-Keefer Fund for New Scientists; and the Peter and Patricia Gruber Award.

 

From Computers to Brains


Dr. Elad Schneidman was born in Jerusalem in 1969. He studied for a B.Sc. in physics and computer science through the Hebrew University’s “Amirim” program for outstanding students before serving in the IDF as a research and development officer. He then worked for a number of high-tech companies and, in 2001, completed his doctorate in the Hebrew University’s Interdisciplinary Center for Neural Computation. After five years of postdoctoral research at Princeton University, Schneidman returned to Israel and joined the Weizmann Institute’s Neurobiology Department. He is married to Hadas Mechoulam, an ophthalmologist, and they have three children.
 
 
Dr. Elad Schneidman.
Life Sciences
English
  • Brain research
  • Elad Schneidman
  • Neural code
  • Neurobiology

Just Add Water

English
 
Prof. David Milstein. Hydrogen in three easy steps

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Take a metal complex. Add water and heat to 100°C for three days, stirring occasionally. Then add a generous amount of light and continue to “simmer” at room temperature for a further two days. The resulting hydrogen and oxygen are now ready to be “served.”
 
This is the gist of a unique new strategy devised by Prof. David Milstein and his colleagues in the Weizmann Institute’s Organic Chemistry Department; and it represents the first steps toward obtaining a clean, sustainable source of hydrogen for fuel. While today’s methods of producing hydrogen using sunlight are inefficient and often discharge chemical waste, the new system relies on a metal complex that is “reset” for reuse at the end of the procedure. In the process, the team demonstrated a new mode of bond generation between oxygen atoms and they even defined the mechanisms by which this takes place. In fact, says Milstein, the production of oxygen gas through the pairing of oxygen atoms that have been split off from water molecules – a crucial step in the process – has proven to be a bottleneck. Their results have recently been published in Science.
 
Nature has taken a very different path to producing free oxygen: It’s a byproduct of the photosynthesis carried out by plants. Spurred on by plants’ “green” example, vast worldwide efforts have been devoted to the creation of artificial photosynthetic systems. The ones Milstein develops are based on metal complexes that serve as catalysts (substances that increase the rate of a chemical reaction without getting used up themselves).
 
The new approach devised by the Weizmann team is divided into a stepwise sequence of reactions, beginning with water splitting. Milstein’s “secret ingredient” is a complex of the element ruthenium designed by his group in previous studies. This is a “smart” synthetic complex composed of a metal center and an organic (carbon-based) component; the two cooperate in cleaving the water molecule. This complex not only breaks the chemical bond between hydrogen and oxygen, but prevents them from getting back together by binding one hydrogen atom to its organic part and the remaining hydrogen and oxygen atoms (an OH group) to its metal part, creating a new metal complex.
 
The second stage – the heat stage – involves heating the resulting complex in water to 100°C, leading to the release of hydrogen gas – a potential source of clean fuel – and creating another chemical structure on the metal complex, this one containing two OH groups.
 
“But the most interesting part is the third, light-driven stage,” says Milstein. “When we exposed the third version of the complex to light at room temperature, not only was oxygen gas produced but the metal complex also reverted back to its original state, and this could be recycled for use in further reactions.”
 
These results have garnered a fair amount of interest in their field, as bonding between two oxygen atoms promoted by a man-made metal complex was previously a very rare event and its mechanism had been a mystery. Milstein and his team succeeded, for the first time, in identifying an unprecedented mechanism for this process. Their experiments indicated that during the third stage, the energy provided by the light causes the two OH groups to get together and form hydrogen peroxide (H2O2), which then quickly breaks up into oxygen and water. “Because hydrogen peroxide is considered a relatively unstable molecule, scientists have generally deemed this step implausible; but we have shown otherwise,” says Milstein. The team also challenged another misconception, providing evidence that the bond between the two oxygen atoms is generated within a single molecule, involving just one metal center, and not between oxygen atoms residing on separate molecules as was commonly thought.
 
So far, Milstein’s team has demonstrated a three-step mechanism for the formation of hydrogen and oxygen from water using light, without the production of chemical waste. For their next study, they plan to combine these stages to create an efficient catalytic system, bringing those in the field of alternative energy one step closer to realizing the goal of a clean, efficient method for producing hydrogen fuel from water using sunlight.
 
Participating in the research were former postdoctoral fellow Dr. Stephan Kohl, research student Leonid Schwartsburd and Yehoshoa Ben-David, all of the Organic Chemistry Department, together with Drs. Lev Weiner, Leonid Konstantinovski, Linda Shimon and Mark Iron of Chemical Research Support.

 

Prof. David Milstein’s research is supported by the Mary and Tom Beck-Canadian Center for Alternative Energy Research; the Helen and Martin Kimmel Center for Molecular Design; and the Bernice and Peter Cohn Catalysis Research Fund. Prof. Milstein is the incumbent of the Israel Matz Professorial Chair of Organic Chemistry.

 
Prof. David Milstein. Hydrogen in three easy steps
Chemistry
English
  • Alternative Energy
  • Catalyst
  • David Milstein
  • Green Chemistry
  • Organic Chemistry

Picking Up Speed

English

Prof. Dan Tawfik. The mutations that drive evolution

Charles Darwin realized that it's not money but mutations that make the world go round. Mutations drive evolution: They alter gene sequences, tweaking the function of their protein products and assuring the adaptability of organisms to ever-changing environments.

In nature, proteins are able to evolve new functions surprisingly rapidly and efficiently. In contrast, scientists who try to evolve proteins in the test tube do not fare as well. One snag lies in the precise 3-D structures proteins must get folded into before they can function. These structures are very fragile, so introducing even a minor mutation can undermine the protein’s stability, causing it to misfold. To protect the organism, many such mutations – including those with the potential to endow proteins with new functions – are purged. “Like throwing the baby out with the bath water, the future potential for adaptation is also destroyed, and this severely limits the rate of protein evolution,” says Prof. Dan Tawfik of the Weizmann Institute’s Biological Chemistry Department.

Scientists are keen on revealing how nature deals with these mutations because the ability to evolve proteins in the laboratory – so-called “directed evolution” – provides a powerful means for engineering tailor-made enzymes (proteins that speed up chemical reactions) with novel properties for a range of industrial, biotechnological and medical applications.

It turns out that in living cells these trouble-prone proteins are accompanied by chaperones – protein babysitters that help newly-synthesized proteins fold into the correct 3-D structures and later save them when they get into hot water – literally. When a cell undergoes such environmental stress as exposure to high temperatures, causing proteins to misfold, high numbers of chaperones are induced to rescue the misfolded proteins and help the cell survive the so-called heat shock.

Tawfik wondered whether these same chaperones could perform a similar function in the lab: keeping mutated proteins out of trouble and thus accelerating directed protein evolution. To find out, postdoctoral fellow Dr. Nobuhiko Tokuriki carried out directed evolution experiments, introducing random mutations in selected enzymes, both in the presence and absence of large amounts of a chaperone from the bacterium E. coli, called GroEL/GroES.

In a research article recently published in Nature and featured in its “Making the Paper” section, Tawfik and Tokuriki showed that the chaperones seemed to buffer the effects of many mutations and, in doing so, were able to save about one-third of the mutated proteins that would otherwise have perished. This, in turn, enabled proteins to acquire twice as many mutations, promoting genetic diversity and accelerating the rate at which they acquired new functions through generations of evolution. What’s more, the evolved proteins that had chaperone help were, on average, 10 times more active and more specifically adapted to their tasks than their chaperoneless cousins.

Tawfik: “These results are quite striking. Although the scientific community suspected that chaperones could play a role in salvaging mutated proteins, there was no systematic evidence to support the idea, let alone the remarkably high extent of their rescue capabilities.”

Two hundred years after Darwin’s birth, this work adds another detail to the evolutionary picture, providing direct evidence that protein stability is, indeed, a major constraint in protein evolution and that buffering mechanisms such as chaperones are key in alleviating such constraints.

In light of this research, chaperones will almost certainly be used routinely by those trying to produce more powerful enzymes for biotechnical applications. Tawfik: “Whether evolving in nature or the lab, if you’re not fast you’ll never make it to the finish line.”

Prof. Dan Tawfik’s research is supported by the J&R Center for Scientific Research; the Willner Family Leadership Institute for the Weizmann Institute of Science; the Sassoon and Marjorie Peress Philanthropic Fund; the Jack Wolgin Prize for Scientific Excellence; Miel de Botton Aynsley, UK; Mario Fleck, Brazil; Mr. and Mrs. Yossie Hollander, Israel; Roberto and Renata Ruhman, Brazil; David Rosenberg, Houston, TX; Charles Rothschild, Brazil; and Rowland Schaefer, New York, NY.

 

A Welcome Surprise

 
Nobuhiko Tokuriki. The only Japanese student

 

 

 

 

 

 

 

 

Nobuhiko (Nobu) Tokuriki became interested in science at a young age – especially evolution. During his undergraduate studies, he learned of directed evolution and knew that was what he wanted to research. Impressed by Tawfik’s work, Nobu contacted him at the University of Cambridge, UK, and asked if he could conduct his postdoctoral studies in Tawfik’s lab. Tawfik agreed, although there was one catch – he had already moved back to Israel to conduct research at the Weizmann Institute. “I had hardly heard of Israel, let alone the Weizmann Institute, before I contacted Danny, but I thought, why not, it could be an interesting experience,” says Nobu. And he was not disappointed: “It was certainly an amazing experience to work in such a fine institute, with many great scientists, lots of activity and a wonderful atmosphere. Also, being the only Japanese student at that time was an experience in itself: Apart from comparing various cultural differences, I also had the honor of being asked to meet a Japanese ambassador, Japanese diplomats and various other visitors from Japan.”

 

Since then, Nobu has come full circle and is continuing his research at the University of Cambridge, UK.

 
Prof. Dan Tawfik. Saving mutations
Life Sciences
English
  • Biological Chemistry
  • Dan Tawfik
  • Protein evolution
  • Protein folding

Spinning Dice, Revolving Doors

English
 

Dr. Barak Dayan. Quantum information processing

“God doesn’t play dice with the world,” remarked Albert Einstein, referring to one of the pillars of quantum theory – randomness. In the quantum world, this property can take a unique twist: Two separate events may be random, yet perfectly linked. It’s as though dice rolled in two different cities always fall at the exact same instant on the same number. Einstein felt this should be impossible, but such “entangled systems” have been observed in a number of labs around the world.

Dr. Barak Dayan, who recently joined the Institute’s Chemical Physics Department, is attracted by the seemingly illogical nature of entangled systems. Though they fly in the face of intuition, such systems form the basis of quantum optics, a field that might revolutionize computing and communication sciences. Quantum information processing, as the new technology is called, will work in profoundly different ways from those that we’re used to. For instance, using entanglement, quantum computers could carry out parallel computations that are impossible in today’s conventional computers. Dayan compares such computing to scanning a large number of suitcases for a bomb. Rather than check them one at a time, a quantum setup could address the whole set of suitcases as an entangled system, revealing the location of the bomb after a drastically smaller number of trials.

But quantum entanglement shares a drawback with other quantum systems: Measurement (or any observation) affects the final result. In practical terms, this means that during the quantum process such systems must be strictly isolated to prevent interactions with the outside world – any such interaction could lead to information “leaking out.” In the systems Dayan devises, an atom is the “computer” and single photons (light particles) are the “input and output” – vehicles for transferring quantum information to and from the atom. “The minimalist design of the system curtails information escape,” he says.

The trick is to control every aspect of the interactions between the atoms and photons. To do this, Dayan gets a single atom to interact with a single photon. This is no trivial feat: Individual photons are quite weak and an exceptionally strong sensor is needed to discern them. And, if this were not enough, the lone atom the photon must aim for is an extremely tiny target. Dayan also means to control the outcome of this get-together – the exact path of the photon, whether the atom absorbs or scatters the photon, how it reacts to the information carried in the light particle, etc. He uses novel technology he helped to develop at the California Institute of Technology (Caltech), consisting of lasers and magnetic fields for manipulating the individual atoms and bringing them into contact with the photons, which are confined within tiny, chip-based ring-like resonators smaller than one-third the width of a human hair.

Dayan aims to investigate interactions between individual photons in which the atom acts as a go-between. This presents a great challenge, as photons normally don’t “speak” to one another. In his postdoctoral work at Caltech, Dayan used the atom-photon interaction in the resonator to create a “revolving door.” Photons could enter the resonator singly, in pairs or threesomes, but they had to leave in single file, one at a time. This study, which appeared in Science, is one of the very few demonstrations to date of interactions between single photons.

An understanding of how to let single photons interact with one another could lead to all-optical switches. In such a switch, one photon could signal to the others “wait a sec, I’m going through.” More importantly, such atom-mediated photon-photon interactions could serve as the basis of logic gates for quantum computers.
 

 
A quantum optic experimental system developed by Dr. Barak Dayan at Caltech. An optic fiber (horizontal line, left) brings light to resonators (light dots appearing in a vertical row on the optic chip, center). Lasers above the chip are used to cool and manipulate single atoms
 
 
 
 
 
 
 
 
 
 
 
 

 

 

 

 

 

 

 

Entangled in the Lab

 
Dr. Barak Dayan was born in Tel Aviv in 1970. Through the elite “Talpiot” academic army project, he completed a B.Sc. in physics and mathematics and an M.Sc. in physics at the Hebrew University of Jerusalem. After leaving the Israel Defense Forces in 1999, he started Ph.D. studies in the group of Prof. Yaron Silberberg of the Weizmann Institute’s Physics of Complex Systems Department. There he took part in initiating and setting up a brand new quantum optics lab. One of his experiments provided some of the first examples ever of interactions between pairs of entangled photons, demonstrating the counter-intuitive mathematical rules that govern entangled systems. During this time, he also planned and taught courses in the Institute’s Young@Science programs.
 
Following postdoctoral research in the quantum optics group of Prof. Jeff Kimble at Caltech, Dayan returned to Israel and joined the Weizmann Institute’s Chemical Physics Department in 2008. Outside the lab, his efforts at science education are aimed at his children, Tamar, aged eight, and Oded, aged three, with whom he loves spending most of his free time.
 

Dr. Barak Dayan’s research is supported by the estate of David Guerchenson.

 
A quantum optic experimental system developed by Dr. Barak Dayan at Caltech. An optic fiber (horizontal line, left) brings light to resonators (light dots appearing in a vertical row on the optic chip, center). Lasers above the chip are used to cool and manipulate single atoms
Space & Physics
English
  • Barak Dayan
  • Chemical Physics
  • Quantum computer
  • Quantum physics›Quantum systems

Cancer’s Ins and Outs

English

 

Prof. Yosef Yarden and Dr. Yaron Mosesson. Derailing cancer prevention

 

 

 

 

 

 

 

 

 

 

Cancer cells are notoriously versatile survivors that exploit normal cellular machinery to their advantage. Weizmann Institute scientists have recently identified a clever “trick” employed by these cells: Apparently, in many of their survival strategies, cancer cells “derail” a particular mechanism that is crucial to the cell’s functioning. Understanding how such derailment is accomplished could lead to new cancer therapies and help to overcome resistance to existing cancer drugs.
 

The mechanism in question, called endocytosis, serves to introduce substances into the cell: First, the cell’s membrane deforms to create a deep dent, like that in the surface of a rubber ball when it’s pressed with a finger. This dent expands and closes in on itself just underneath the cell membrane, forming a bubble that detaches and is transported to various locations inside the cell. A substance enclosed within the bubble – for example, a nutrient or a receptor molecule – can move in this manner from the cell’s surface into its interior. Ultimately, most substances transported in such bubbles are recycled or destroyed in an organelle called the lysosome.
 
Research by Prof. Yosef Yarden of the Weizmann Institute’s Biological Regulation Department, together with his former graduate student Dr. Yaron Mosesson and other colleagues at Weizmann and elsewhere, suggests that derailed endocytosis facilitates cancer development at different stages. For example, when the inner lining of the lungs or milk ducts is undergoing renewal, endocytosis periodically eliminates the receptors for growth-stimulating molecules, called growth factors, on the cell’s surface. These receptors are sucked into a bubble to be destroyed inside the lysosome, preventing abnormal cellular growth. But if endocytosis is deficient, these receptors can turn into cancer-causing machines: They continue to convey growth signals, leading to carcinoma of the lung, breast or other organs. Overly active endocytosis, on the other hand, can also lead to cancer by destroying the molecular “glue” that holds cells together and prevents them from proliferating excessively. Likewise, in metastasis – the deadly spread of cancer throughout the body – abnormal endocytosis plays an important role: It eliminates the cancer cells’ attachment to tissues, allowing them to migrate and spread.
 
But how exactly is endocytosis derailed? In a study published in Developmental Cell, Mosesson and other members of Yarden’s team, in collaboration with Tel Aviv University, the Technion – Israel Institute of Technology and the University of Porto in Portugal, have identified a previously unknown component of endocytosis in human beings. The molecule, a protein called Lst2, facilitates the endocytosis of growth factor receptors. When Lst2 is lacking, these receptors fail to complete the process, getting trapped in a cancer-promoting routine: They evade the lysosome and move back to the cell surface, where they can start another cycle of growth.
 
A better understanding of endocytosis might help develop new drugs that would block cancer at various stages. Such understanding could also help improve the penetration of existing drugs into malignant cells, thereby overcoming tumor resistance to certain forms of chemotherapy.

 

Prof. Yosef Yarden’s research is supported by the M.D. Moross Institute for Cancer Research; the Aharon Katzir-Katchalsky Center; the Goldhirsh Foundation; and the estate of Benjamin Bernstein. Prof. Yarden is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology.
 
(l-r) Prof. Yosef Yarden and Dr. Yaron Mosesson. In the bubble
Life Sciences
English
  • Biological Regulation
  • Cancer
  • Cancer cell survival
  • Yosef Yarden›Yosef Yarden

Shorter and Faster

English
 
Dr. Nirit Dudovich and Dror Shafir. Ultra-fast lasers freeze molecular action

 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
Like top athletes, leading scientists continually test the limits of human ability. While an athlete trains to break the 100-meter sprint record, for instance, a scientist might be found attempting to break the record for catching sight of the fastest movements known, such as those of the electrons moving inside molecules and atoms. For years scientists had referred to these movements as instantaneous. Are they truly instantaneous? Or has the available scientific equipment simply not been advanced enough to detect electrons in the act of getting from one place to another? By pushing the bounds of laser optic technology, physicists today are beginning to reveal electron movements taking place within unimaginably short timeframes.
 
Ultrafast pulses of laser light replace camera shutters when filming the very fastest activities; for instance, chemical reactions in which molecules break apart into smaller molecules. Like the fast-shutter cameras used to capture still shots of a basketball player in mid-dunk, the flashes of laser light serve to “freeze” molecular actions at various stages.
 
The faster the natural process, the shorter and faster the laser pulses must be to capture it on film. For a number of years, the fastest lasers available produced flashes down to the length of a femto-second – a millionth of a billionth of a second. This is rapid enough to observe many molecular processes. But, the movements of the electrons in a molecule are faster still and the technology was not up to capturing them.
 
“The limits on the capabilities of lasers stem from a basic, physical restriction,” says Dr. Nirit Dudovich, who joined the Weizmann Institute’s Physics of Complex Systems Department two years ago. “The single period of a light wave determines the lower limit for the duration of a laser pulse. A femtosecond pulse is the shortest that one can get from wavelengths in the visible range.”
 
Unwilling to stop pushing the physical boundaries, scientists have found a way to overcome this. An experiment with this method begins with powerful laser pulses lasting just a few femtoseconds aimed at a molecule, “tearing” out one of its electrons – a quantum phenomenon called tunneling. The electron, freed from its orbit around the molecule, takes a short “trip.” This escape is shortlived, and the electron soon returns to its home molecule. As the electron slips back into place, a photon (light particle) is emitted. The entire process evolves during less than one optical cycle of visible light; the duration of the emitted light is around an attosecond (a billionth of a billionth of a second).
 
This ability to capture the movements of electrons circling atoms or molecules in “freeze frames” has ushered in a new field of research. But Dudovich has taken that research a step further: “Why use lasers to trace other molecules, I thought, when so much could be learned about the process through the interaction of light with the molecules on which the laser itself is based?” In other words, she’s turned the camera back on itself to image the basic process in which photons are emitted and electrons change position.
 
Dudovich and her research team have been exploring ways to control the direction of the tunneling electrons so as to get them to reenter the molecule or atom from different angles. Like medical imaging that builds a three-dimensional picture from a series of “slices,” such an approach could give researchers an unprecedented view of molecules and molecular processes. In a paper that recently appeared in Nature Physics, the researchers demonstrated that by changing the polarization of the beam used to tear the electron from the atom, one can reroute the electron’s path and direct the angle of its reentry.
 
With this method, Dudovich and her team succeeded in characterizing the distribution of electrons in an atom. “In the future,” she says, “our goal is to measure the time, as well, and to integrate time with location. In other words, we’ll be able to produce a sort of movie that records electrons moving through various processes and chemical reactions as they take place.”
 
Dr. Nirit Dudovich’s research is supported by the Chais Family Fellows Program for New Scientists; the Lord Sieff of Brimpton Memorial Fund; the IPA Prize for a Promising New Scientist funded by Dana and John R. Burgess and Stacey and Gregg Steinberg; the estate of Jeanne K. Goldstein; the estate of Esther Ragosin; the estate of Julius and Hanna Rosen; the Charles and Julia Wolf Philanthropic Fund; and the Wolfson Family Charitable Trust.
 
Dr. Nirit Dudovich and Dror Shafir. Ultra-fast lasers freeze molecular action
Space & Physics
English
  • Laser
  • Nirit Dudovich
  • Physics of Complex Systems

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