Stoltz Wins Grant from the Camille and Henry Dreyfus Foundation

Professor of Chemistry Brian Stoltz has been awarded a $120,000 grant from the Camille and Henry Dreyfus Foundation's Postdoctoral Program in Environmental Chemistry. The grant, distributed over two years, provides funds for a principal investigator to appoint a postdoctoral fellow to work on "innovative fundamental research in the chemical sciences or engineering related to the environment."

Stoltz's lab focuses on using chemical synthesis to develop new reactions and strategies for manufacturing complex molecules. In collaboration with the laboratories of Paul Wennberg, the R. Stanton Avery Professor of Atmospheric Chemistry and Environmental Science and Engineering, and Mitchio Okumura, professor of chemical physics, Stoltz's group will use the Dreyfus Foundation grant to fund a postdoctoral scholar and an interdisciplinary project that merges the fields of synthetic, organic, and environmental reaction chemistry.

"We plan to employ organic synthesis as a tool to help address unresolved questions that have eluded traditional methods of experimental atmospheric chemistry, including the identification of oxidation mechanisms that lead to the formation of organic particulate matter and to the regeneration of atmospheric oxidant radicals," says Stoltz. "In the process, we hope to educate a postdoctoral scholar and expose them to a broad range of scientific disciplines and skills by applying techniques from synthetic and atmospheric chemistry in an interdisciplinary setting."

Fourteen other Caltech professors have received this grant since its inception in 1996.

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Monday, March 2, 2015
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The Secret Life of a Snowflake

Caltech Biochemist Sheds Light on Structure of Key Cellular 'Gatekeeper'

Facing a challenge akin to solving a 1,000-piece jigsaw puzzle while blindfolded—and without touching the pieces—many structural biochemists thought it would be impossible to determine the atomic structure of a massive cellular machine called the nuclear pore complex (NPC), which is vital for cell survival.

But after 10 years of attacking the problem, a team led by André Hoelz, assistant professor of chemistry, recently solved almost a third of the puzzle. The approach his team developed to do so also promises to speed completion of the remainder.

In an article published online February 12 by Science Express, Hoelz and his colleagues describe the structure of a significant portion of the NPC, which is made up of many copies of about 34 different proteins, perhaps 1,000 proteins in all and a total of 10 million atoms. In eukaryotic cells (those with a membrane-bound nucleus), the NPC forms a transport channel in the nuclear membrane. The NPC serves as a gatekeeper, essentially deciding which proteins and other molecules are permitted to pass into and out of the nucleus. The survival of cells is dependent upon the accuracy of these decisions.

Understanding the structure of the NPC could lead to new classes of cancer drugs as well as antiviral medicines. "The NPC is a huge target of viruses," Hoelz says. Indeed, pathogens such as HIV and Ebola subvert the NPC as a way to take control of cells, rendering them incapable of functioning normally. Figuring out just how the NPC works might enable the design of new drugs to block such intruders.

"This is an incredibly important structure to study," he says, "but because it is so large and complex, people thought it was crazy to work on it. But 10 years ago, we hypothesized that we could solve the atomic structure with a divide-and-conquer approach—basically breaking the task into manageable parts—and we've shown that for a major section of the NPC, this actually worked."

To map the structure of the NPC, Hoelz relied primarily on X-ray crystallography, which involves shining X-rays on a crystallized sample and using detectors to analyze the pattern of rays reflected off the atoms in the crystal.

It is particularly challenging to obtain X-ray diffraction images of the intact NPC for several reasons, including that the NPC is both enormous (about 30 times larger than the ribosome, a large cellular component whose structure wasn't solved until the year 2000) and complex (with as many as 1,000 individual pieces, each composed of several smaller sections). In addition, the NPC is flexible, with many moving parts, making it difficult to capture in individual snapshots at the atomic level, as X-ray crystallography aims to do. Finally, despite being enormous compared to other cellular components, the NPC is still vanishingly small (only 120 nanometers wide, or about 1/900th the thickness of a dollar bill), and its highly flexible nature prohibits structure determination with current X-ray crystallography methods.

To overcome those obstacles, Hoelz and his team chose to determine the structure of the coat nucleoporin complex (CNC)—one of the two main complexes that make up the NPC—rather than tackling the whole structure at once (in total the NPC is composed of six subcomplexes, two major ones and four smaller ones, see illustration). He enlisted the support of study coauthor Anthony Kossiakoff of the University of Chicago, who helped to develop the engineered antibodies needed to essentially "superglue" the samples into place to form an ordered crystalline lattice so they could be properly imaged. The X-ray diffraction data used for structure determination was collected at the General Medical Sciences and National Cancer Institutes Structural Biology Beamline at the Argonne National Laboratory.

With the help of Caltech's Molecular Observatory—a facility, developed with support from the Gordon and Betty Moore Foundation, that includes a completely automated X-ray beamline at the Stanford Synchrotron Radiation Laboratory that can be controlled remotely from Caltech—Hoelz's team refined the antibody adhesives required to generate the best crystalline samples. This process alone took two years to get exactly right.

Hoelz and his team were able to determine the precise size, shape, and the position of all atoms of the CNC, and also its location within the entire NPC.

The CNC is not the first component of the NPC to be fully characterized, but it is by far the largest. Hoelz says that once the other major component—known as the adaptor–channel nucleoporin complex—and the four smaller subcomplexes are mapped, the NPC's structure will be fully understood.

The CNC that Hoelz and his team evaluated comes from baker's yeast—a commonly used research organism—but the CNC structure is the right size and shape to dock with the NPC of a human cell. "It fits inside like a hand in a glove," Hoelz says. "That's significant because it is a very strong indication that the architecture of the NPC in both are probably the same and that the machinery is so important that evolution has not changed it in a billion years."

Being able to successfully determine the structure of the CNC makes mapping the remainder of the NPC an easier proposition. "It's like climbing Mount Everest. Knowing you can do it lowers the bar, so you know you can now climb K2 and all these other mountains," says Hoelz, who is convinced that the entire NPC will be characterized soon. "It will happen. I don't know if it will be in five or 10 or 20 years, but I'm sure it will happen in my lifetime. We will have an atomic model of the entire nuclear pore."

Still, he adds, "My dream actually goes much farther. I don't really want to have a static image of the pore. What I really would like—and this is where people look at me with a bit of a smile on their face, like they're laughing a little bit—is to get an image of how the pore is moving, how the machine actually works. The pore is not a static hole, it can open up like the iris of a camera to let something through that's much bigger. How does it do it?"

To understand that machine in motion, he adds, "you don't just need one snapshot, you need multiple snapshots. But once you have one, you can infer the other ones much quicker, so that's the ultimate goal. That's the dream."

Along with Hoelz, additional Caltech authors on the paper, "Architecture of the Nuclear Pore Complex Coat," include postdoctoral scholars Tobias Stuwe and Ana R. Correia, and graduate student Daniel H. Lin. Coauthors from the University of Chicago Department of Biochemistry and Molecular Biology include Anthony Kossiakoff, Marcin Paduch and Vincent Lu. The work was supported by Caltech startup funds, the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, the 54th Mallinckrodt Scholar Award of the Edward Mallinckrodt, Jr. Foundation, and a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research.

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Why Comets Are Like Deep Fried Ice Cream

Astronomers tinkering with ice and organics in the lab may have discovered why comets are encased in a hard, outer crust.

Using an icebox-like instrument nicknamed Himalaya, the researchers show that fluffy ice on the surface of a comet would crystalize and harden as the comet heads toward the sun and warms up. As the water-ice crystals form, becoming denser and more ordered, other molecules containing carbon would be expelled to the comet's surface. The result is a crunchy comet crust sprinkled with organic dust.

"A comet is like deep fried ice cream," said Murthy Gudipati, a principal scientist at JPL and corresponding author of a recent study appearing in The Journal of Physical Chemistry. "The crust is made of crystalline ice, while the interior is colder and more porous. The organics are like a final layer of chocolate on top."

The lead author of the study is Antti Lignell, a postdoctoral scholar in Caltech's Division of Chemistry and Chemical Engineering, who formerly worked with Gudipati at JPL. Caltech manages JPL for NASA.

Read the full story at JPL News.

Written by Whitney Clavin

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Six from Caltech Elected to National Academy of Engineering

Six members of the Caltech community—Caltech professors Harry Atwater, Mory Gharib (PhD '83), Robert Grubbs, and Guruswami (Ravi) Ravichandran, and JPL staff members Dan M. Goebel and Graeme L. Stephens—have been elected to the National Academy of Engineering (NAE), an honor considered among the highest professional distinctions accorded to an engineer. The academy welcomed 67 new American members and 12 foreign members this year. Included among the new class are four Caltech alumni, Dana Powers (BS '70, PhD '75), Michael Tsapatsis (MS '91, PhD '94), Vigor Yang (PhD '84), and Ajit Yoganathan (PhD '78).

Harry Atwater, the Howard Hughes Professor of Applied Physics and Materials Science and director of the Resnick Sustainability Institute, was cited for his contributions to plasmonics—the study of plasmons, coordinated waves of electrons on the surfaces of metals. Atwater is developing plasmonic devices for controlling light on a nanometer scale. Such devices could be important for the eventual creation of quantum computers and more efficient photovoltaic cells in solar panels.

Mory Gharib is the vice provost for research and the Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering. His election citation notes his contributions to fluid flow visualization techniques and the engineering of bioinspired medical devices. Gharib's biomechanical studies are often coupled with medical engineering; for example, by studying the fluid dynamics of the human cardiovascular system, he and his group are better able to develop new types of prosthetic heart valves.

Dan M. Goebel, a senior research scientist at JPL, was honored for his contributions to low-temperature plasma sources for thin-film manufacturing, plasma materials interactions, and electric propulsion.

Robert Grubbs, the Victor and Elizabeth Atkins Professor of Chemistry and corecipient of the 2005 Nobel Prize in Chemistry, was elected for the development of catalysts that have enabled commercial products. For example, Grubbs and his team developed a new method for synthesizing organosilanes—basic chemical building blocks. Normally these molecules are made with expensive and rare precious metals, but Grubbs's group has found a way to catalyze the reaction using a cheap and abundant potassium compound.

Guruswami (Ravi) Ravichandran is the John E. Goode, Jr., Professor of Aerospace, professor of mechanical engineering, and director of the Graduate Aerospace Laboratories (GALCIT). He is cited by the NAE for his contributions to the mechanics of dynamic deformation, damage, and failure of engineering materials. Ravichandran has studied the behavior of polymers under high pressures and strains, and how the peeling of an adhesive material—like Scotch Tape—may be modeled as a crack propagating in a medium.

Graeme L. Stephens, the director of JPL's Center for Climate Sciences, was elected by the Academy for the elucidation of Earth's cloud system and radiation balance.

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Potassium Salt Outperforms Precious Metals As a Catalyst

A team of Caltech chemists has discovered a method for producing a group of silicon-containing organic chemicals without relying on expensive precious metal catalysts. Instead, the new technique uses as a catalyst a cheap, abundant chemical that is commonly found in chemistry labs around the world—potassium tert-butoxide—to help create a host of products ranging from new medicines to advanced materials. And it turns out that the potassium salt is more effective than state-of-the-art precious metal complexes at running very challenging chemical reactions.

"We have shown for the first time that you can efficiently make carbon–silicon bonds with a safe and inexpensive catalyst based on potassium rather than ultrarare precious metals like platinum, palladium, and iridium," says Anton Toutov, a graduate student working in the laboratory of Bob Grubbs, Caltech's Victor and Elizabeth Atkins Professor of Chemistry. "We're very excited because this new method is not only 'greener' and more efficient, but it is also thousands of times less expensive than what's currently out there for making useful chemical building blocks. This is a technology that the chemical industry could readily adopt."

The finding marks one of the first cases in which catalysis—the use of catalysts to make certain reactions occur faster, more readily, or at all—moves away from being a practice that is fundamentally unsustainable. While the precious metals in most catalysts are rare and could eventually run out, potassium is an abundant element on Earth.

The team describes its new "green" chemistry technique in the February 5 issue of the journal Nature. The lead authors on the paper are Toutov and Wen-bo (Boger) Liu, a postdoctoral scholar at Caltech. Toutov recently won the Dow Sustainability Innovation Student Challenge Award (SISCA) grand prize for this work, in a competition held at Caltech's Resnick Sustainability Institute.

"The first time I spoke about this at a conference, people were stunned," says Grubbs, corecipient of the 2005 Nobel Prize in Chemistry. "I added three slides about this chemistry to the end of my talk, and afterward it was all anyone wanted to talk about."

Coauthor Brian Stoltz, professor of chemistry at Caltech, says the reason for this strong response is that while the chemistry the catalyst drives is challenging, potassium tert-butoxide is so seemingly simple. The white, free-flowing powder—similar to common table salt in appearance—provides a straightforward and environmentally friendly way to run a reaction that involves replacing a carbon–hydrogen bond with a carbon–silicon bond to produce molecules known as organosilanes.

These organic molecules are of particular interest because they serve as powerful chemical building blocks for medicinal chemists to use in the creation of new pharmaceuticals. They also hold promise in the development of new materials for use in products such as LCD screens and organic solar cells, could be important in the development of new pesticides, and are being incorporated into novel medical imaging tools.

"To be able to do this type of reaction, which is one of the most-studied problems in the world of chemistry, with potassium tert-butoxide—a material that's not precious-metal based but still catalytically active—was a total shocker," Stoltz says.

The current project got its start a couple of years ago when coauthor Alexey Fedorov—then a postdoctoral scholar in the Grubbs lab (now at ETH Zürich)—was working on a completely different problem. He was trying to break carbon–oxygen bonds in biomass using simple silicon-containing compounds, metals, and potassium tert-butoxide, which is a common additive. During that process, he ran a control experiment—one without a metal catalyst—leaving only potassium tert-butoxide as the reagent. Remarkably, the reaction still worked. And when Toutov—who was working with Fedorov—analyzed the reaction further, he realized that in addition to the expected products, the reaction was making small amounts of organosilanes. This was unexpected since organosilanes are very challenging to produce.

"I thought that was impossible, so I went back and checked it many times," Toutov says. "Sure enough, it checked out!"

Bolstered by the finding, Toutov refined the reaction so that it would create only a single desired organosilane in high yield under mild conditions, with hydrogen gas as the only byproduct. Then he expanded the scope of the reaction to produce industrially useful chemicals such as molecules needed for new materials and derivatives of pharmaceutical substances.

Having demonstrated the broad applicability of the reaction, Toutov teamed up with Liu from Stoltz's group to further develop the chemistry for the synthesis of building blocks relevant to the preparation of new human medicines, a field in which Stoltz has been active for over a decade.

But before delving too deeply into additional applications, the chemists sought the assistance of Nathan Dalleska, director of the Environmental Analysis Center in the Ronald and Maxine Linde Center for Global Environmental Science at Caltech to perform one more test with a mass spectrometer that geologists use to detect extremely minute quantities of metals. They were trying to detect some tiny amount of those precious metals that could be contaminating their experiments—something that might explain why they were getting these seemingly impossible results from potassium tert-butoxide alone.

"But there was nothing there," says Stoltz. "We made our own potassium tert-butoxide and also bought it from various vendors, and yet the chemistry continued to work just the same. We had to really convince ourselves that it was true, that there were no precious metals in there. Eventually, we had to just decide to believe it."

So far, the chemists do not know why the simple catalyst is able to drive these complex reactions. But Stoltz's lab is part of the Center for Selective C–H Functionalization, a National Science Foundation–funded Center for Chemical Innovation that involves 23 research groups from around the country. Through that center, the Caltech team has started working with Ken Houk's computational chemistry group at UCLA to investigate how the chemistry works from a mechanistic standpoint.

"It's pretty clear that it's functioning by a mechanism that is totally different than the way a precious metal would behave," says Stoltz. "That's going to inspire some people, including ourselves hopefully, to think about how to use and harness that reactivity."

Toutov says that unlike some other catalysts that stop working or become sensitive to air or water when scaled up from the single-gram scale, this new catalyst seems to be robust enough to be used at large, industrial scales. To demonstrate the industrial viability of the process, the Caltech team used the method to synthesize nearly 150 grams of a valuable organosilane—the largest amount of this chemical product that has been produced by a single catalytic reaction. The reaction required no solvent, generated hydrogen gas as the only byproduct, and proceeded at 45°C—the lowest reported temperature at which this reaction has successfully run, to date.

"This discovery just shows how little we in fact know about chemistry," says Stoltz. "People constantly try to tell us how mature our field is, but there is so much fundamental chemistry that we still don't understand."

Kerry Betz, an undergraduate student at Caltech, is a coauthor on the paper, "Silylation of C–H bonds in aromatic heterocycles by an Earth-abundant metal catalyst." The work was supported by the National Science Foundation. The Resnick Sustainability Institute at Caltech, Dow Chemical, the Natural Sciences and Engineering Research Council of Canada, and the Shanghai Institute of Organic Chemistry provided graduate and postdoctoral support. Fedorov's work on the original reaction was supported by BP. 

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Friday, February 13, 2015
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Backpocket Barnburner: A Lightning Quick Overview of Educational Theory

Caltech Professors Named Fellows of the AAAS

Caltech Professor of Astronomy George Djorgovski and chemist Bruce Brunschwig are among the 401 newly elected fellows of the American Association for the Advancement of Science (AAAS) for 2014.

The AAAS was formed in 1848 with the mission of "advancing science, engineering, and innovation throughout the world for the benefit of all people." The annual tradition of electing fellows began in 1874 to recognize scientists for their contributions toward this mission.

"The AAAS performs an essential role of promoting and protecting science and its benefits for society. This has never been more important than it is now," says Djorgovski, director of the Center for Data-Driven Discovery at Caltech. He was elected by his scientific peers to the AAAS's Section on Astronomy for his "leadership of the Virtual Observatory and the emerging field of astroinformatics, and considerable body of work on surveys and transient discovery." Astronomical data is exponentially growing in complexity and volume; the Virtual Observatory is an open, web-based research environment intended to organize, maintain, and explore the rich information content within these datasets.

"Science is being transformed by computing and information technology, and astronomy has been at the forefront of these developments," says Djorgovski.

Brunschwig, director of the Molecular Materials Research Center (MMRC) at Caltech, was elected to the AAAS's Section on Chemistry for his "pioneering contributions to the theoretical and physical understanding of electron transfer and its application to artificial photosynthesis." The MMRC is home to state-of-the-art instrumentation that facilitates cutting-edge interdisciplinary research in the fields of chemistry, surface science, and materials science. The center currently hosts myriad projects, including work on artificial photosynthesis and solar energy conversion.

"Bruce Brunschwig is a model for us to aspire to with his dedication to scholarship and his natural curiosity and inquisitiveness," says Brunschwig's colleague Nate Lewis, the George L. Argyros Professor of Chemistry at Caltech and the scientific director of the Joint Center for Artificial Photosynthesis. "His election as a fellow to the AAAS is well deserved."

Caltech is currently home to 42 fellows of the AAAS.

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Saturday, January 24, 2015
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