Harry Gray Awarded for Lifetime of Basic Research in Chemistry and Advances in Solar Fuel

For decades of breakthroughs in bioinorganic and inorganic photochemistry powering his current work in renewable fuels, Harry Gray, the Beckman Professor of Chemistry and founding director of the Beckman Institute at Caltech, has been named the recipient of the 2009 Welch Award in Chemistry. The award is presented annually by the Houston-based Welch Foundation for lifetime achievement in basic research.

"Harry Gray is a gifted researcher, teacher, and statesman for chemistry," said Dennis Hendrix, chairman of the Welch Foundation. "He has touched almost every aspect of inorganic chemistry in his 45-year career and helped cofound the fields of biological inorganic chemistry and inorganic photochemistry."

Early in his career, Gray developed ligand field theory of inorganic electronic structures, insights still widely used today. He found that the bonding models he had developed for inorganic substances also were useful in understanding many biological processes, leading to the creation of the new field of biological inorganic chemistry.

He moved on to study electron transfer, respiration, and photosynthesis. In the early 1980s, his group made a major discovery when they found that molecules do not have to be in close contact to transfer electrons as previously thought, but instead two metal atoms could complete the transfer over "long" distances of as much as two or three nanometers and across 20 atoms or more. This discovery is significant in that the longer distances provide the opportunity to capture and store the energy created by the electron moving from one molecule to the next, rather than simply generating heat that is wasted in the "short" distance transfers.

This breakthrough forms the basis for photosynthetic systems that can store sunlight's energy as a chemical fuel. The fuel then can be used to make electricity when needed. His current work is exploring how best to duplicate nature's photosynthesis, the process by which plants turn sunlight into food and concurrently produce the oxygen essential to life. Gray and his team are exploring the use of abundant inorganic (nonliving) materials and sunlight to generate hydrogen fuel and clean water economically on a large scale.

The Welch Foundation supports science through research and departmental grants, funding of academic chairs, an annual chemical conference and support for other chemistry-related programs. Gray will receive the award in October at a banquet hosted by the Welch Foundation in Houston. At that time, he will be presented with the Welch Award gold medallion and the $300,000 prize.

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Jon Weiner
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New Radiation-free Targeted Therapy Detects and Eliminates Breast-Cancer Tumors in Mice

Caltech researcher helps develop technique that homes in on aggressive, difficult-to-treat HER2+ breast cancer cells

PASADENA, Calif.--Combining a compound known as a gallium corrole with a protein carrier results in a targeted cancer therapy that is able to detect and eliminate tumors in mice with seemingly fewer side effects than other breast-cancer treatments, says a team of researchers from the California Institute of Technology (Caltech), the Israel Institute of Technology (Technion) and the Cedars-Sinai Medical Center.

A paper describing their work is highlighted in this week's issue of the online edition of the Proceedings of the National Academy of Sciences (PNAS).

Corroles have very similar structures to the porphyrin molecules used in a well-studied cancer treatment known as photodynamic therapy, or PDT, in which porphyrin compounds injected into the body are exposed to specific wavelengths of laser light. The light prompts the porphyrins to produce active, tumor-killing oxygen radicals.

The difference between porphyrins and corroles, says Harry Gray, Caltech's Arnold O. Beckman Professor of Chemistry and founding director of the Beckman Institute, is that some corroles don't require a laser boost to turn lethal. "The striking thing about gallium corroles is that they apparently kill cancer cells in the dark," says Gray. "We don't yet know exactly how this works, but what we've seen so far tells us that it does work."

He notes that "ongoing work in our laboratories focuses on testing our leading hypotheses for elucidating the mechanism of action."

In the experiments described in the PNAS paper, the team paired a gallium corrole with a carrier protein, then aimed it at cells that carry the human epidermal growth factor receptor 2 (HER2). The presence of a HER2 receptor is the hallmark of about 25 percent of breast cancers, and marks those tumors as particularly aggressive and difficult to treat.

In trials in mice, the targeted corrole was able to shrink tumors at doses five times lower than that of the standard chemotherapeutic agent for HER2-positive tumors, a drug called doxorubicin. In contrast with doxorubicin, the corrole was injected into the bloodstream, rather than directly into the tumor.

"We looked at three groups of mice with human tumors," explains paper coauthor Lali Medina-Kauwe, an assistant professor of medicine at the David Geffen School of Medicine at UCLA, and a faculty research scientist in the Department of Biomedical Science at Cedars-Sinai Medical Center in Los Angeles. "In one, we introduced just the protein carrier, without the corrole; tumor growth in those mice did not change. In other mice, we gave the corrole without the carrier protein; this led to some tumor suppression. But it was the last group, the ones that got the corrole with the carrier protein, that experienced the most therapeutic effect."

"The fact that we can target this compound means we can give it at very low concentrations," adds coauthor Daniel Farkas, director of Cedar-Sinai's Minimally Invasive Surgical Technologies Institute. "Using lower concentrations means less toxicity. Doxorubicin tends to have significant heart toxicity; this therapy seems likely to be much less damaging to the heart."

In addition, adds Medina-Kauwe, targeted compounds can seek out tumors wherever they may be. "One of the beauties of targeting," she says, " is that we can go after metastatic tumors that are too small to be seen."

These targeted gallium corroles are not only effective, they're also easy to study, notes Zeev Gross, the Reba May & Robert D. Blum Academic Chair at Technion, the Israeli Institute of Technology, in Haifa, and another of the paper's coauthors. "In most cases, if people want to get a closer look at a drug in vivo, they have to attach a fluorescent probe to it--and that turns it into a different molecule. But in our case, the active molecule we're tracking does the fluorescing. We get to track the original, unmodified molecule and are hence able to follow its distribution among different organs in live animals."

The difficulty in getting to this point, notes Gray, is that corroles have been challenging to synthesize. "Then Zeev came up with a powerful synthetic method to make corroles," he says. "We went from being able to make a couple of milligrams in two years to being able to make two grams in two days. It really puts corroles on the map."

Gray and Gross further add, "It is truly fulfilling to see how the close collaboration between our research groups at Caltech and the Technion, which started 10 years ago with a focus on developing the fundamental science of corroles, led to pharmaceutical utility when we joined forces with Medina-Kauwe and Farkas, who are experts in cellular biology and biomedical imaging technologies."

The work described in the paper, "Tumor detection and elimination by a targeted gallium corrole," was supported by grants from the National Science Foundation, the National Institutes of Health, the U.S. Department of Defense, Susan G. Komen for the Cure, the Donna and Jesse Garber Award, the Gurwin Foundation, the United States-Israel Binational Science Foundation, and by the U.S. Navy Bureau of Medicine and Surgery.

In addition to the researchers mentioned above, the other scientists contributing to this work include senior scientist Atif Mahammed from Technion, and research associates Hasmik Agadjanian and Altan Rentsendorj, postdoc Vinod Valluripalli, and graduate students Jun Ma and Jae Youn Hwang from Cedars-Sinai.

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Contact:    Lori Oliwenstein
        (626) 395-3631

Visit the Caltech Media Relations website at http://pr.caltech.edu/media.

Lori Oliwenstein
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Caltech Scientists Create New Enzymes for Biofuel Production

Enzymes are important step toward cheaper biofuels

Researchers at the California Institute of Technology (Caltech) and world-leading gene-synthesis company DNA2.0 have taken an important step toward the development of a cost-efficient process to extract sugars from cellulose--the world's most abundant organic material and cheapest form of solar-energy storage. Plant sugars are easily converted into a variety of renewable fuels such as ethanol or butanol.

In a paper published this week in the early edition of the Proceedings of the National Academy of Sciences, Frances H. Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering and Biochemistry at Caltech, and her colleagues report the construction of 15 new highly stable fungal enzyme catalysts that efficiently break down cellulose into sugars at high temperatures. Previously, fewer than 10 such fungal cellobiohydrolase II enzymes were known. In addition to their remarkable stabilities, Arnold's enzymes degrade cellulose over a wide range of conditions.

Biofuels are made by converting renewable materials--for example, corn kernels, wood chips left over from pulp and paper production, prairie grasses, and even garbage--into fuels and chemicals. Most biofuels used today are made from the fermentation of starch from corn kernels. That process, although simple, is costly because of the high price of the corn kernels themselves.

Agricultural waste, such as corn stover (the leaves, stalks, and stripped cobs of corn plants, left over after harvest), is cheap. These materials are largely composed of cellulose, the chief component of plant-cell walls. Cellulose is far tougher to break down than starch. An additional complication is that while the fermentation reaction that breaks down corn starch needs just one enzyme, the degradation of cellulose requires a whole suite of enzymes, or cellulases, working in concert.

The cellulases currently used industrially, all of which were isolated from various species of plant-decaying filamentous fungi, are both slow and unstable, and, as a result, the process remains prohibitively expensive. "Even a two-fold reduction in their cost could make a big difference to the economics of renewable fuels and chemicals," says Arnold.

Arnold and Caltech postdoctoral scholar Pete Heinzelman created the 15 new enzymes using a process called structure-guided recombination. Using a computer program to design where the genes recombine, the Caltech researchers "mated" the sequences of three known fungal cellulases to make more than 6,000 progeny sequences that were different from any of the parents, yet encoded proteins with the same structure and cellulose-degradation ability.

By analyzing the enzymes encoded by a small subset of those sequences, the Caltech and DNA2.0 researchers were able to predict which of the more than 6,000 possible new enzymes would be the most stable, especially under higher temperatures (a characteristic called thermostability).

Thermostability is a requirement of efficient cellulases, because at higher temperatures--say, 70 or even 80 degrees Celsius--chemical reactions are more rapid. In addition, cellulose swells at higher temperatures, which makes it easier to break down. Unfortunately, the known cellulases from nature typically won't function at temperatures higher than about 50 degrees Celsius.

"Enzymes that are highly thermostable also tend to last for a long time, even at lower temperatures," Arnold says. "And, longer-lasting enzymes break down more cellulose, leading to lower cost."

Using the computer-generated sequences, coauthor Jeremy Minshull and colleagues from DNA2.0 of Menlo Park, California, synthesized actual DNA sequences, which were transferred into yeast in Arnold's laboratory. The yeast produced the enzymes, which were then tested for their cellulose-degrading ability and efficiency. Each of the 15 new cellulases reported in the PNAS paper was more stable, worked at significantly higher temperatures (70 to 75 degrees Celsius), and degraded more cellulose than the parent enzymes at those temperatures.

"This is a really nice demonstration of the power of synthetic biology," Arnold says. "You can rapidly generate novel, interesting biological materials in the laboratory, and you don't have to rely on what you find in nature. We just emailed DNA2.0 sequences based on what we pulled out of a database and our recombination design, and they synthesized the DNA. We never had to go to any organism to get them. We never touched a fungus."

Next, the researchers plan to use the structure-guided recombination process to perfect each of the half-dozen or so cellulases that make up the soup of enzymes required for the industrial degradation of cellulose. "We've demonstrated the process on one of the components. Now we have to create families of all of the other components, and then look for the ideal mixtures for each individual application," Arnold says, with the ultimate goal of creating a cost-efficient recipe for cellulosic biofuel.

"If you think about it, energy is the biggest industry there is," Arnold says. "If we can replace foreign oil with renewable biofuels, that's an enormous contribution. And that replacement is slow right now because these enzymes are just too expensive."

The work in the paper, "A Family of Thermostable Fungal Cellulases Created by Structure-Guided Recombination," was supported by the Army-Industry Institute for Collaborative Biotechnologies and the Caltech Innovation Institute.

Kathy Svitil
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Caltech and UCSD Researchers Shed Light on How Proteins Find Their Shapes

The researchers bring together theoretical models and experimental data to explain protein folding

PASADENA, Calif.--Researchers from the California Institute of Technology (Caltech) and the University of California at San Diego (UCSD) have brought together UCSD theoretical modeling and Caltech experimental data to show just how amino-acid chains might fold up into unique, three-dimensional functional proteins.

Their insights were recently published in the February 10 issue of the Proceedings of the National Academy of Sciences (PNAS).

The paper details the matching of a series of protein-folding models created by the UCSD team (led by Peter Wolynes, UCSD professor of chemistry and biochemistry and physics) with experimental data gathered using a novel technique created by the Caltech team (led by Faculty Associate in Chemistry Jay Winkler and Harry Gray, Caltech's Arnold O. Beckman Professor of Chemistry and founding director of the Beckman Institute).

The Winkler-Gray method of watching proteins as they crumple and fold involves the use of a picosecond camera that captures fluorescent flashes as a laser pulse excites a donor probe, which emits light and transfers that light to an acceptor probe. The distance between the donor and acceptor change as the amino-acid chain transforms itself into a three-dimensional protein.

In the PNAS paper, the two groups combined the Caltech experimental technique--first described in a 2002 paper published in the Journal of the American Chemical Society--with Wolynes's protein-folding models to see if they could come up with the precise folding pattern of cytochrome c, a protein that is part of the mitochondrial electron-transfer chain that turns food into cellular energy.

At first the models and the experimental data seemed to be describing two entirely different things, according to Winkler. "The researchers had to account for charge-charge interactions between amino acids that appear to be important--the way that like charges repel and opposite charges attract," he explains. "And they had to consider the hydrophobic interactions--the way that oily parts of the proteins like to stick together but are repelled by the watery parts. When their models took account of these interactions, it fit the experimental data."

"It was the first time anyone has been able to develop a theoretical model able to account for the results we've been getting with our time-resolved energy-transfer experiments," adds Gray.

Other coauthors on the PNAS paper, entitled "Electrostatic effects on funneled landscapes and structural diversity in denatured protein ensembles," are Patrick Weinkam from UCSD and Ekaterina Pletneva, formerly at Caltech and now at Dartmouth College.

This work was supported by grants from the National Institutes of Health and by a National Science Foundation Center for Theoretical Biological Physics grant.

Lori Oliwenstein

Self-Regulating Molecular "Transformers" Control the Intracellular Delivery of Proteins

PASADENA, Calif.--Scientists from the California Institute of Technology (Caltech) have uncovered the Transformer like properties of molecules responsible for carrying and depositing proteins to their correct locations within cells. The research could eventually lead to novel treatments for diseases that result from flaws in protein delivery as well as the development of new types of antibiotics.

Shu-ou Shan, an assistant professor of chemistry at Caltech, and her colleagues looked specifically at a pair of proteins that sort cellular proteins and deliver them to their destinations--a process that is essential for establishing and maintaining cellular organization. The proteins, known as the signal recognition particle (SRP) and the SRP receptor (SR), are responsible for shuttling more than a third of all cellular proteins to their targets, including the insulin protein. The SRP/SR system is present in all three kingdoms of life, from humans and other animals, to plants and fungi, to bacteria and primitive archaean organisms.

By tracking the movement of fluorescently tagged molecules, Shan and her colleagues were able to track the behavior of SRP and SR during the protein pick-up and delivery process.

They found that the binding of a protein cargo by the SRP molecule triggered the accelerated assembly of a molecular complex containing SRP, the cargo, and the SR protein. The SRP-SR complex then delivered the cargo to the cell membrane. Once there, the SRP-SR complex spontaneously changed its shape and deposited the cargo at the membrane, like a tiny Transformer toy morphing from a semi-truck delivering goods into a forklift that unloads them. The scientists described their discovery in a recent paper in the Proceedings of the National Academy of Sciences.

"The Transformer analogy is very appropriate," says Shan. "The 'truck' is able to sense that cargo has been loaded and starts the engine running without instructions from a driver. It can also sense that it has arrived at the destination and, without workers coming to unload the goods, is able to switch on another system to do that by itself." This self-sufficient system, she says, represents "a new way that biology builds switches to regulate complex cellular pathways."

Shan and colleagues also found that the presence of protein cargo delays the breakdown of a small-molecule energy carrier called guanosine triphosphate, or GTP, from which the SRP and SR harvest the energy to form a complex with each other and to undergo all their molecular transformations. "GTP hydrolysis is like a timer that allows the SRP-SR complex to exist for a specified period of time before turning it off. By delaying this timer, the SRP-SR complex persists about 10 times longer than it would without the cargo. This ensures that there is sufficient time for the cargo to be properly delivered to the membrane," Shan says.

"Understanding which steps are important for protein delivery by the SRP could allow the development of medications that prevent diseases that result from defects in the pathway," Shan says. For example, prion disease can be caused by tiny snippets of misfolded prion proteins that accumulate in the cytoplasm of cells when the SRP pathway does not work properly. The accumulation of cytoplasmic prions leads to the degeneration of neurons, and the eventual death of the affected organism."

The research could also lead to the development of novel artificial delivery systems that can shuttle particular proteins to specific locations, and may spur the design of new types of antibiotics that target the SRP protein in bacteria. Blocking the bacterial SRP will indeed kill bacteria, Shan says, but because humans have SRP proteins, it "will also likely affect the operation of cells in your body. Detailed mechanistic studies are required to figure out the difference between the mammalian and the bacteria SRP pathway, and find places to intervene where the bacterial SRP is uniquely susceptible."

Shan's paper, "Multiple conformational switches in a GTPase complex control co-translational protein targeting," was coauthored by Xin Zhang, a graduate student at Caltech, and Christiane Schaffitzel and Nenad Ban from the Swiss Federal Institute of Technology. The work was funded by the National Institutes of Health and the Swiss National Science Foundation.



Kathy Svitil

Caltech 4D Microscope Revolutionizes the Way We Look at the Nano World

PASADENA, Calif.-- More than a century ago, the development of the earliest motion picture technology made what had been previously thought "magical" a reality: capturing and recreating the movement and dynamism of the world around us. A breakthrough technology based on new concepts has now accomplished a similar feat, but on an atomic scale--by allowing, for the first time, the real-time, real-space visualization of fleeting changes in the structure and shape of matter barely a billionth of a meter in size.

Such "movies" of atomic changes in materials of gold and graphite, obtained using the technique, are featured in a paper appearing in the November 21 issue of the journal Science. (4D microscopy videos can be viewed at http://ust.caltech.edu/movie_gallery/.) A patent on the conceptual framework of this approach was granted to the California Institute of Technology (Caltech) in 2006.

The new technique, dubbed four-dimensional (4D) electron microscopy, was developed in the Physical Biology Center for Ultrafast Science and Technology, directed by Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics at Caltech, and winner of the 1999 Nobel Prize in Chemistry.

Zewail was awarded the Nobel Prize for pioneering the science of femtochemistry, the use of ultrashort laser flashes to observe fundamental chemical reactions--atoms uniting into molecules, then breaking apart back into atoms--occurring at the timescale of the femtosecond, or one millionth of a billionth of a second. The work "captured atoms and molecules in motion," Zewail says, akin to the freeze-frame stills snapped by 19th-century photographer Eadweard Muybridge of a galloping horse (which proved for the first time that a horse does indeed lift all four hooves off the ground as it gallops) and other moving objects.

Snapshots of molecules in motion "gave us the time dimension," Zewail says, "but what we didn't have was the dimensions of space, the structure. We didn't know what the horse looked like. Did it have a long tail? Beautiful eyes? My dream since 1999 was to come up with a way to look not just at time but also at the spatial domain; to see the architecture of a complex system at the atomic scale, as it changes over time, be it for physical or biological matter."

Scientists can observe the static structure of objects with a resolution that is better than a billionth of a meter in length using electron microscopes, which generate a stream of individual electrons that scatter off objects to produce an image. Electrons are used to visualize the smallest of objects, on the atomic scale, because the wavelength of the radiation source used by a microscope must be shorter than the space between the atoms. This can be accomplished using electrons, and in particular--because the wavelength of an electron shrinks as its velocity increases--by electrons that have been accelerated to dizzying speeds.

But just having electrons isn't sufficient to capture the behavior of atoms in both space and time; the electrons have to be carefully doled out, so that they arrive at the sample at specific time intervals. Zewail and his colleagues have achieved this by introducing the fourth dimension of time into high-resolution electron microscopy, in what has been termed ultrafast "single-electron" imaging, where every electron trajectory is precisely controlled in time and space.

The resulting image produced by each electron represents a femtosecond still at that moment in time. Like the frames in a film, the sequential images generated by many millions of such images can be assembled into a digital movie of motion at the atomic scale.

As reported in the Science paper, Zewail and colleagues applied their new 4D electron microscopy to observe the behavior of the atoms in superthin sheets of gold and graphite. Graphite, the material in pencils, consists of layers of carbon atoms locked into a sheet-like array. The atoms move in a unique and coherent way on the femtosecond timescale.

However, the researchers found that on a slightly longer, picosecond (one thousandth of a billionth of a second) scale, the graphite nanosheets produce sound waves. In the images, they directly visualized the elastic movements of the sheets and determined the force holding them together, which is described by a stress-strain property known as "Young's modulus." The 4D movies produced from the frames revealed the behavior in space and time.

In a second paper in the current issue of the journal Nano Letters, Zewail and his colleagues described their visualization of the changes in a nanometer-thick graphite membrane on a longer time scale, up to a thousandth of a second. The researchers first blasted the sample with a pulse of heat. The heated carbon atoms began to vibrate in a random, nonsynchronized fashion. Over time, however, the oscillations of the individual atoms became synchronized as different modes of the material locked in phase, emerging to become a heartbeat-like "drumming." Digital video, slowed down more than a billion times, illustrates this nano-drumming mechanical phenomenon, which displays a well-defined resonance that is nearly 100 times higher than can be detected by the human eardrum.

"With this 4D imaging technique, atomic-scale motions, which lead to structural, morphological, and nanomechanical phenomena, can now be visualized directly, and hopefully understood," says Zewail, who is now expanding the research to biological imaging within cells in collaboration with Grant Jensen, an associate professor of biology at Caltech.

The researchers are currently using the 4D microscope to image the components of cells, such as proteins and ribosomes, the cellular machinery that makes proteins. They have already produced images of a stained rat cell and, more recently, of a protein crystal and cell in vitreous water. "The goal is to enhance the structural resolution in the images of these biomaterials by taking single-pulse snapshots before they move or deteriorate, and to follow their dynamics in real time," Zewail says.

In a recent commentary on the development, Sir John Thomas of Cambridge University, who is a world-renowned expert in electron microscopy, said the invention and its applications are "revolutionary." "The door is now open for myriad explorations in the physical and biological sciences," Thomas added.

"The sequences of images produced by this technique are remarkable," says David Tirrell, chair of Caltech's Division of Chemistry and Chemical Engineering. "They not only provide unprecedented insights into molecular and materials behavior--they do so in an especially satisfying fashion by allowing direct observation of complex structural changes in real space and real time. These experiments will lead us to fundamentally new ways of thinking about molecules and materials."

"Advances in imaging, concepts, and technology for visualization are fundamental to progress in diverse scientific and engineering fields," says Edward M. Stolper, Caltech's provost. "Caltech has made a commitment to leadership across the many physical and biological disciplines in which imaging plays a critical role. Ahmed's pioneering work is trailblazing new frontiers of science and technology."

Two centers supported the development of this technology: the Laboratory for Molecular Science, funded by the National Science Foundation, and the Physical Biology Center, funded by Gordon and Betty Moore Foundation. The work was also supported by grants from the Air Force Office of Scientific Research, the National Science Foundation, and the National Institutes of Health.



Kathy Svitil

Four Caltech Faculty Members Named Among 100 Chemical Engineers of the Modern Era

American Institute of Chemical Engineers lauds Frances Arnold, Mark Davis, Julia Kornfield, and John Seinfeld

PASADENA, Calif.--Four members of the 11-member chemical engineering faculty at the California Institute of Technology (Caltech) were honored by the American Institute of Chemical Engineers (AIChE) in their list of 100 Chemical Engineers of the Modern Era, published in the October issue of their magazine, Chemical Engineering Progress.

"Now in its second century, the chemical engineering profession--like the Institute--has been shaped and sustained by the achievements, leadership and imagination of thousands of engineers," the AIChE wrote in introducing its list.

The four Caltech chemical engineers named were

* Frances H. Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering and Biochemistry, who was recognized for "research on engineering biological systems, particular proteins and genetic regulatory networks, (e.g., using novel enzymes to catalyze cellulose hydrolysis)." The AIChE also noted that Arnold is the only woman to have been elected to all three branches of the National Academies: the National Academy of Engineering (in 2000), the Institute of Medicine (in 2004), and the National Academy of Sciences (in 2008).

* Mark E. Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering, who was recognized for "pioneering work in new catalytic materials and chemical sensors using ceramics and electronic materials."

* Julia A. Kornfield, professor of chemical engineering, who was recognized for "work on polymer blend dynamics; flow alignment of liquid-crystalline and block polymers; physical aspects of new biomedical materials."

* John H. Seinfeld, the Louis E. Nohl Professor and professor of chemical engineering, who was recognized for "developing first models describing urban air quality" and for being "one of first to describe linkage between urban ozone and global climate change."

"I'm very proud that my colleagues have been recognized in this way by the most important professional organization in the field of chemical engineering. Their selection reflects well on the Caltech approach to things, which is to stay small while maintaining the highest possible standards in education and research," says David Tirrell, chair of Caltech's Division of Chemistry and Chemical Engineering.

"At Caltech, I'm inspired to work on the hardest problems, because the students here can solve them," adds Frances Arnold. "This honor, awarded to almost half our department, certainly recognizes that."

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Lori Oliwenstein
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Caltech Engineers Build First-Ever Multi-Input "Plug-and-Play" Synthetic RNA Device

Could one day be used to detect tumor cells or create targeted gene therapies

PASADENA, Calif.--Engineers from the California Institute of Technology (Caltech) have created a "plug-and-play" synthetic RNA device--a sort of eminently customizable biological computer--that is capable of taking in and responding to more than one biological or environmental signal at a time.

In the future, such devices could have a multitude of potential medical applications, including being used as sensors to sniff out tumor cells or determine when to turn modified genes on or off during cancer therapy.

A synthetic RNA device is a biological device that uses engineered modular components made of RNA nucleotides to perform a specific function--for instance, to detect and respond to biochemical signals inside a cell or in its immediate environment.

Created by Caltech's Christina Smolke, assistant professor of chemical engineering, and Maung Nyan Win, postdoctoral scholar in chemical engineering, the device is made up of modules comprising the RNA-based biological equivalents of engineering's sensors, actuators, and information transmitters. These individual components can be combined in a variety of different ways to create a device that can both detect and respond to what could conceivably be an almost infinite number of environmental and cellular signals.

This modular device processes these inputs in a manner almost identical to the logic gates used in computing; it can perform AND, NOR, NAND, and OR computations, and can perform signal filtering and signal gain operations. Smolke and Win's creation is the first RNA device that can handle more than one incoming piece of biological information. "There's been a lot of work done in single-input devices," notes Smolke. "But this is the first demonstration that a multi-input RNA device is possible."

Their work was published in the October 17 issue of the journal Science.

The modular--or plug-and-play--nature of the device's design also means that it can be easily modified to suit almost any need. "Scientists won't have to redesign their system every time they want the RNA device to take on a new function," Smolke explains. "This modular framework allows you to quickly put a device together, then just as easily swap out the components for other ones and get a completely different kind of computation. We could generate huge libraries of well-defined sensors and assemble many different tailored devices from such component libraries."

Although the work in the Science paper was done in yeast cells, Smolke says they have already shown that they can translate to mammalian cells as well. This makes it possible to consider using these devices in a wide variety of medical applications.

For instance, ongoing work in Smolke's laboratory is looking at the packaging of these RNA devices--configured with the appropriate sensor modules--in human T cells. The synthetic device would literally be placed within the cell to detect certain signals--say, one or more particular biochemical markers that are given off by tumor cells. If those biomarkers were present, the RNA device would signal the T cell to spring into action against the putative tumor cell.

Similarly, an RNA device could be bundled alongside a modified gene as part of a targeted gene therapy package. One of the problems gene therapy faces today is its lack of specificity--it's hard to make sure a modified gene meant to fix a problem in the liver reaches or is inserted in only liver cells. But an RNA device, Smolke says, could be customized to detect the unique biomarkers of a liver cell--or, better yet, of a diseased liver cell--and only then give the modified gene the go-ahead to do its stuff.

The work described in this paper, "Higher-Order Cellular Information Processing with Synthetic RNA Devices," was supported by grants from the Center for Biological Circuit Design at the California Institute of Technology, the Arnold and Mabel Beckman Foundation, and the National Institutes of Health. Smolke and Win have a patent application pending on their synthetic RNA device.

For more information on Smolke's work, visit http://www.che.caltech.edu/groups/cds/index.htm

Lori Oliwenstein
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Caltech Researcher Awarded $10 Million Grant

PASADENA, Calif.-- Brian M. Stoltz, the Ethel Wilson Bowles and Robert Bowles Professor of Chemistry at the California Institute of Technology (Caltech), has been awarded a $10 million grant from the King Abdullah University of Science and Technology (KAUST).

Stoltz, whose work is focused on developing new strategies for the synthesis of complex molecules with interesting structural, biological, and physical properties that may lead to useful biological and medical applications, is one of 12 international scientists chosen to receive the award as part of the KAUST Global Research Partnership (GRP) Investigator competition. The GRP program is designed to fund research in areas of science and technology that are of particular importance to Saudi Arabia and the region, such as water desalination, renewable and sustainable next-generation energy sources, salt-tolerant plants, durable and environmentally friendly construction materials, and solar technology.

Each investigator was scrutinized by a panel of 14 world-renowned scientists, including Caltech's former provost Steven E. Koonin, chief scientist at British Petroleum, and evaluated based on their record of achievement to date and the relevance of their proposed research to the mission areas of KAUST, which include energy and environment; materials science and bioengineering; biosciences; and applied mathematics and computational science.

Stoltz was recognized for his efforts to discover and develop new oxidation reaction processes of potential utility for the chemical, polymer, and pharmaceutical industries. The new methods employ organometallic catalysts in conjunction with molecular oxygen, instead of the toxic metals that are normally used. These new catalytic reactions also provide avenues of reactivity that are simply unavailable using older techniques.

"Caltech is honored that KAUST and its committee of esteemed scientists selected Brian Stoltz after their extensive search for the world's most promising science and technology researchers," says Caltech president Jean-Lou Chameau. "This generous award will significantly advance Brian's efforts in chemical synthesis and nontoxic catalysts, and also reminds us of the global impact that our scientists are making with their research," adds Chameau.

"This is an enormous boost for our research program and my students and I couldn't be happier that the KAUST GRP has entrusted us with this honor," Stoltz says. "I am excited to work with KAUST and be a part of this very unique endeavor. It will be an exciting time here and at KAUST!"

Each investigator will spend at least three weeks per year on the KAUST campus in Saudi Arabia, participating in the research and academic life of the University.

KAUST is an international graduate-level research university, "dedicated to inspiring a new age of scientific achievement in the Kingdom, across the region and around the globe," being built on the Red Sea at Thuwal, approximately 50 miles north of Saudi Arabia's second-largest city, Jeddah. The 36-million-square-meter core campus is set to open in September 2009. For more information, visit http://www.kaust.edu.sa.

With an outstanding faculty, including five Nobel laureates, and such off-campus facilities as the Jet Propulsion Laboratory, Palomar Observatory, and the W. M. Keck Observatory, the California Institute of Technology is one of the world's major research centers. Caltech offers instruction in science and engineering for a student body of approximately 900 undergraduates and 1,200 graduate students who maintain a high level of scholarship and intellectual achievement. Caltech is a private university in Pasadena, California. For more information, visit http://www.caltech.edu.

Kathy Svitil
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Caltech Engineers Build Mini Drug-Producing Biofactories in Yeast

PASADENA, Calif.-- Researchers at the California Institute of Technology have developed a novel way to churn out large quantities of drugs, including antiplaque toothpaste additives, antibiotics, nicotine, and even morphine, using mini biofactories--in yeast. 

A paper describing the research, now available online, will be featured as the cover article of the September issue of Nature Chemical Biology.

Christina D. Smolke, an assistant professor of chemical engineering at Caltech, along with graduate student Kristy Hawkins, genetically modified common baker's yeast (Saccharomyces cerevisiae) so that it contained the genes for several plant enzymes. The enzymes allow the yeast to produce a chemical called reticuline, which is a precursor for many different classes of benzylisoquinoline alkaloid (BIA) molecules. The BIA molecules are a large group of chemically intricate compounds, such as morphine, nicotine, and codeine, which are naturally produced by plants.

BIA molecules exhibit a wide variety of pharmacological activities, including antispasmodic effects, pain relief, and hair growth acceleration. Other BIAs have shown anticancer, antioxidant, antimalarial, and anti-HIV potential.

"There are estimated to be thousands of members in the BIA family, and having a source for obtaining large quantities of specific BIA molecules is critical to gaining access to the diverse functional activities provided by these molecules," says Smolke, whose lab focuses on using biology as a technology for the synthesis of new chemicals, materials, and products. However, the natural plant sources of BIAs accumulate only a small number of the molecules, usually "end products" like morphine and codeine that, while valuable, can't be turned into other compounds, thus limiting the availability of useful new products.

To their reticuline-producing yeast, Smolke and Hawkins added the genes for other enzymes, from both plants and humans, which allowed the yeast to efficiently generate large quantities of the precursors for sanguinarine, a toothpaste additive with antiplaque properties; berberine, an antibiotic; and morphine.

The researchers are now in the process of engineering their yeast so that they will turn these precursor molecules into the final, pharmacologically useful molecules. "But even the intermediate molecules that we are producing can exhibit important and valuable activities, and a related area of research will be to examine more closely the pharmacological activities of these metabolites and derivatives now that pure sources can be obtained," says Smolke, who estimates that her system could be used for the large-scale manufacture of BIA compounds in one to three years.

Smolke and Hawkins also plan to extend their research to the production of BIAs that don't normally exist in nature.

"If one thinks of these molecules as encoding functions that are of interest to us, the ability to produce nonnatural alkaloids will provide access to more diverse functions and activities. By expanding to nonnatural alkaloids, we can search for molecules that provide enhanced activities, new activities, and not be limited by the activities that have been selected for in nature," says Smolke.

"Our work has the potential to result in new therapeutic drugs for a broad range of diseases. This work also provides an exciting example of the increased complexity with which we are engineering biological systems to address global societal challenges," she says.

The research was supported by the Center for Biological Circuit Design at Caltech and the National Institutes of Health.


Kathy Svitil
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