What they didn’t expect to discover, however, was that one of these “crosstalk” proteins is actually an essential autophagy protein, called Atg12. In addition to its previously known function in autophagy, the scientists found – through various screening and gene knockdown procedures – that Atg12 also has a drastic effect on the activation of apoptosis. Without Atg12, the apoptotic responses of cells were significantly attenuated. "This was quite surprising as, until now, this protein has only been known to function in autophagy," says Rubinstein. But finding the influential protein was the relatively easy part; the harder task was to understand how Atg12 is able to control apoptosis.

With the help of Miriam Eisenstein of the Chemical Research Support Department, Kimchi and Rubinstein identified a region in the Atg12 protein that is similar to one seen in apoptotic proteins. This region promotes apoptosis by binding to and inhibiting a family of anti-apoptotic proteins called Bcl-2. Could the region on the autophagy protein function in the same way? By employing a special technique to identify protein binding partners, the scientists discovered, as they reported in Molecular Cell, that Atg12 is, indeed, able to partner with Bcl-2 and its extended family members, and the end result is apoptosis. They also found that the role Atg12 plays in apoptosis is independent of its role in autophagy: Disrupting its apoptotic function did not impair autophagy and, conversely, disrupting the autophagic pathway did not impair its apoptotic function.

This research may, among other things, have implications for cancer treatment. In many cases, cancer cells shut down the apoptotic process by elevating levels of Bcl-2, in effect enabling the cancer to grow unhindered. Because initial results of the study suggest that Atg12 binds Bcl-2 using a unique mechanism – different from that of other apoptotic proteins – Atg12 might be considered as a possible basis for anti-cancer drugs that target Bcl-2.

The next question the scientists will endeavor to answer is: Why does the cell use the same protein to carry out two different tasks? "We speculate that in certain situations in which a cell is under stress, it first induces autophagy to try and save itself. If this fails, however, it switches to apoptosis to sacrifice itself for the sake of the organism. By employing the same protein, there would be a direct connection between autophagy and apoptosis, making the process much quicker and more efficient," says Rubinstein.

 

Prof. Adi Kimchi’s research is supported by the Helen and Martin Kimmel Institute for Stem Cell Research. Prof. Kimchi is the incumbent of the Helena Rubinstein Professorial Chair in Cancer Research.
 

To the scientists’ surprise, the X-ray and radio observations yielded no significant data; the archival study did not reveal what was there beforehand. But, like the dog in the Sherlock Holmes story that didn’t bark, this lack turned out to be a significant clue: It allowed them to eliminate several of the proposed scenarios for the setup that might have caused the explosion.

These scenarios fall into two broad categories, both of them involving ancient, dense stars called white dwarfs. In one of them, two white dwarfs merge, and their combined mass becomes unstable, ending in a thermonuclear blast. In the other, the heavy white dwarf siphons off material from a companion star until it exceeds its stable weight limit, again causing an explosion. Proposed companion stars run the gamut from huge, gaseous red giants to smaller, sun-like stars.

The PTF results, including an analysis of the material thrown off in the blast and of the “shock breakout” that takes place as the light released in the shockwave passes through the mass of erupting material, showed that the exploding star was, as predicted, a white dwarf. The picture that emerged was of an extremely compact star – its diameter much smaller than that of our sun. And while the team didn’t manage to discount either category, they set an upper limit on the size of a possible companion, showing it could not have been a particularly large star – excluding, for instance, a red giant scenario.

“Although we can’t rule out a white dwarf merger,” says Ofek, “our results point to another likely scenario, in which a medium-range star – close to our sun’s size – supplied the white dwarf with the extra material needed to turn it into a supernova.”

Dr. Eran Ofek, who recently joined the Weizmann Institute’s Particle Physics and Astrophysics Department after six years in California, started working almost as soon as his plane landed in Israel: “We arrived on August 23^rd, and on the 24^th we got notification of the new supernova. Instead of setting up house or shopping for a car, I was on line with other astrophysicists arranging observation time and collecting data.”

Fortunately for Ofek, who is married and the father of two small daughters, his wife, Dr. Orly Gnat, was forgiving. She is also an astrophysicist, who is currently undertaking postdoctoral research at the Hebrew University of Jerusalem. Ofek and Gnat met when they were undergraduates at Tel Aviv University. After receiving their doctorates from Tel Aviv University, they went on to postdoctoral positions at the California Institute of Technology (Caltech) and have now returned to Israel.

At Caltech, Ofek was involved in setting up the Palomar Transient Factory – a project based at the Palomar Observatory in California that searches for transient bursts of light indicating stellar explosions. The Weizmann Institute is a partner in PTF, along with scientists from all over the US and Europe. Ofek was responsible for the telescopes’ robotic capabilities: These autonomous seekers “decide” for themselves which parts of the sky to search and analyze their observations independently before notifying team members of possible supernova sightings. Ofek: “The PTF has identified more supernovae than any other survey, and we have expanded the number of known types of supernovae, as well.”

 

 

Dr. Eran Ofek's research is supported by the Willner Family Leadership Institute.

 

      


 

In the experiment, the researchers inserted electrodes into the nasal passages of volunteers and measured the nerves’ responses to different smells in various sites. Each measurement actually captured the response of thousands of smell receptors, as these are densely packed on the membrane. The scientists found that the strength of the nerve signal varies from place to place on the membrane. It appeared that the receptors are not evenly distributed; rather, that they are grouped into distinct sites, each engaging most strongly with a particular type of scent. Further investigation showed that the intensity of a reaction was linked to the odor’s place on the pleasantness scale. A site where the nerves reacted strongly to a certain agreeable scent also showed strong reactions to other pleasing smells and vice versa: The nerves in an area with a high response to one unpleasant odor reacted similarly to other disagreeable smells. The implication is that a pleasantness scale is, indeed, an organizing principle for our smell organ.

But does our sense of smell really work according to this simple principle? Natural odors are composed of a large number of molecules – roses, for instance, release 172 different odor molecules. Nonetheless, says Sobel, the most dominant of those determine which sites on the membrane will react the most strongly, while the other substances make secondary contributions to the smelling experience.

“We uncovered a clear correlation between the pattern of nerve reaction to various smells and the pleasantness of those smells. As in sight and hearing, the receptors for our sense of smell are spatially organized in a way that reflects the nature of the sensory experience,” says Sobel. In addition, the findings confirm the idea that our experience of a smell as nice or nasty is hardwired into our physiology, and not purely the result of individual preference. Sobel doesn’t discount the idea that individuals may experience smells differently. He theorizes that cultural context and personal experience may cause a certain amount of reorganization in smell perception over a person’s lifetime.

This research was carried out by Drs. Hadas Lipid, Sagit Shushan and Anton Plotkin in the group of Prof. Noam Sobel, together with Dr. Elad Schneidman of the Weizmann Institute’s Neurobiology Department, Dr. Yehudah Roth of Wolfson Hospital in Holon, Prof. Hillary Voet of the Hebrew University of Jerusalem and Prof. Thomas Hummel of Dresden University, Germany.

 

 

Dr. Elad Schneidman's research is supported by the Jeanne and Joseph Nissim Foundation for Life Sciences Research; Mr. and Mrs. Lawrence Feis, Winnetka, IL; the
Peter and Patricia Gruber Award; and the J & R Foundation.
 

 

“The marriage of water to protein is really quite a complex process. By combining novel structural-biophysical tools with protein engineering, we managed to advance our understanding of nature’s designs,” says Sagi.

Does water play additional roles in the actions of this enzyme? How does it participate in other biomolecular processes? For Sagi, Havenith and their teams, this study is just the beginning. They believe that understanding the precise role of water in the actions of many different types of biological molecules may be especially useful for designing drugs, including some that they themselves are in the process of developing.

 

Prof. Irit Sagi’s research is supported by the Spencer Charitable Fund; the Leona M. and Harry B. Helmsley Charitable Trust; Cynthia Adelson, Canada; Mireille Steinberg, Canada; the Leonard and Carol Berall Post Doctoral Fellowship; and the Ilse Katz Institute for Material Sciences and Magnetic Resonance Research. Prof. Sagi is the incumbent of the Maurizio Pontecorvo Professorial Chair. 
 

 

 

Here, the team of protein mapmakers ran into a few snags. For one, it is difficult to track down freely roaming protein molecules long enough to analyze them. Haran devised a trap: He encapsulated each protein molecule within a vesicle and tethered it to a surface, thus immobilizing the protein so that measurements could be carried out. Another catch was that the fluorescent dye loses its fluorescence within a few seconds, not providing enough time for the protein folding event to be traced in its entirety. To tackle this problem, the team took thousands of single-protein molecules and analyzed short traces of folding events, each one starting at a different point in time. At this stage, the researchers resembled a biographer whose pages have suddenly been blown by a gust of wind; to return things to the proper order, they developed a statistical analysis that "stitched" together the short sequences of folding events in their correct chronological sequence.
 

The scientists discovered, as recently reported in Nature Communications, that for the protein they analyzed, there are a total of six possible states that lead to its 3-D structure. The route this protein chose depended on such external factors as temperature or chemicals: The higher the chemical concentration, for example, the more likely the protein was to opt for the longer, more arduous route – folding into all six of the possible conformations in sequential order before reaching its destination. At lower concentrations, the protein was able to follow easier routes, taking shortcuts that bypassed different conformational states while still ending up at the same folded structure.

Despite the challenges in designing a method for following the activities of individual protein molecules (as opposed to standard methods that average the behavior of thousands of molecules), the techniques the team developed enabled them to obtain a highly detailed picture, with all its variations, of protein folding. They now plan to explore different protein "landscapes" to gain a deeper understanding: Is there a general folding rule that applies to all proteins?  And what are the forces that guide a molecule to fold?

 

Prof. Gilad Haran’s research is supported by the Carolito Stiftung. Prof. Haran is the incumbent of the Hilda Pomeraniec Memorial Professorial Chair.