Nobel Laureate Ahmed Zewail Named United States Science Envoy

Caltech scientist will promote science and technology partnerships among nations

PASADENA, CALIF. - Nobel Laureate Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics at the California Institute of Technology (Caltech), has been named an envoy in the new U.S. Science Envoy Program, created to foster science and technology collaborations between the United States and nations throughout the Middle East, North Africa, and South and Southeast Asia. Zewail, who was also appointed to President Obama's Council of Advisors on Science and Technology earlier this year, is one of three eminent Americans who will serve as the first scientist-diplomats in the new program.

Secretary of State Hillary Clinton announced the appointment of "three of America's leading scientists" in a major address on November 3 in Marrakesh, Morocco. She described the program as one of several partnerships in the key areas of economic opportunity, science and technology, and education that are being launched in the wake of President Obama's speech last June at Cairo University, in which he promised a "new beginning" in America's relationship with Muslim communities around the world.

"It is a great honor and humbling responsibility to take on such a challenge in a tumultuous and changing world," said Zewail, who received the 1999 Nobel Prize in Chemistry for groundbreaking research into how atoms join together to form molecules. "After years of research on the dynamics of chemical bonds, I look forward to helping to forge new bonds among nations."

The Egyptian-born Zewail will serve as science envoy to 10 nations of the Middle East, where, according to the State Department, he will "engage counterparts, deepen and develop partnerships in all areas of science and technology, and foster meaningful collaboration to meet the greatest challenges facing the world today in health, energy, the environment, as well as in water and resource management."

"Ahmed Zewail is an ideal choice for science envoy," said Caltech president Jean-Lou Chameau. "He brings to the post superb scientific credentials and an abiding commitment to promoting science and technology for both its own sake and the betterment of society, and he is held in high esteem throughout the world. I am delighted that he will have the opportunity to serve both our nation and the international community in this capacity."

Zewail is internationally known for his work in femtosecond chemistry, in which he pioneered the use of ultrafast laser techniques to record atoms in the act of making and breaking molecular bonds-the basis of all chemical reactions-on the timescale at which such reactions actually occur, about one millionth of a billionth of a second. He currently directs the Physical Biology Center for Ultrafast Science and Technology at Caltech, with a focus on the development of four-dimensional microscopy, a new field established to visualize the behavior in space and time of matter at the nanoscale.

Zewail has a long-standing interest in global affairs, particularly as they relate to science, technology, and higher education, and his commentaries have appeared in Britain's Independent and the Wall Street Journal, among other publications. In a piece published earlier this fall in the Boston Globe and the International Herald Tribune, he called on Muslim nations to join with the West in new science and technology partnerships, an agenda that he will now be in a unique position to advance as U.S. science envoy.

The Caltech professor's numerous honors include the Albert Einstein World Award of Science, the Benjamin Franklin Medal, the Robert A. Welch Award, the Leonardo da Vinci Award, the Wolf Prize, and the King Faisal Prize. He has been awarded the Order of the Grand Collar of the Nile, Egypt's highest state honor, and has been featured on postage stamps issued to honor his contributions to science and humanity. He holds honorary degrees from 35 universities around the world, and is an elected member of many professional academies and societies, including the National Academy of Sciences, the Royal Society of London, and the Swedish, Russian, and French academies.

Zewail's fellow envoys are Bruce Alberts, president of the National Academy of Sciences from 1993 to 2005, and Elias Zerhouni, director of the U.S. National Institutes of Health from 2002 to 2008. Alberts, professor emeritus of biochemistry at the University of California, San Francisco, and editor in chief of Science magazine, will serve as the envoy to South and Southeast Asia. Zerhouni, a native of Algeria and professor of radiology and biomedical engineering at Johns Hopkins University, will be the envoy to North Africa.

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Caltech and Dow Chemical Team Up in Solar Materials Effort

Collaboration includes the creation of Dow Graduate Fellowship in Chemical Sciences and Engineering

PASADENA, Calif.—The California Institute of Technology (Caltech) and the Dow Chemical Company today announced a new solar-research collaboration aimed at developing the use of semiconductor materials that are less expensive and more abundant than those used in many of today's solar cells.

In addition, they announced the creation of the Dow Chemical Company Graduate Fellowship in Chemical Sciences and Engineering.

The fellowship will be granted to a second- or third-year doctoral student who shows excellence in research, leadership, and interpersonal effectiveness, and whose research program aligns with broad areas of interest to Dow, such as alternative energy sources, the development of novel specialty chemicals, and the investigation of new polymer systems. Dow's $500,000 gift will be matched by $250,000 in funds from the Gordon and Betty Moore Matching Program.

Each recipient will be selected by the chair of the Division of Chemistry and Chemical Engineering, and will hold the fellowship for up to two years.

"We are pleased that Dow and Caltech are building this relationship to support innovative research as a basis for new technologies," says Jacqueline K. Barton, the division's current chair.

The solar-research collaboration will be a four-year, $4.2 million effort to explore earth-abundant materials for solar-energy applications. The project is led by applied physicist Harry Atwater, Caltech's Howard Hughes Professor, and chemist Nate Lewis, Caltech's George L. Argyros Professor.

"In combining the R&D strengths of Dow and Caltech, we have created a powerful alliance for innovation in the field of photovoltaics," says Bill Banholzer, executive vice president and chief technology officer of Dow. "This alliance will allow the best scientists the opportunity to work together to achieve the kinds of breakthrough technologies that will be game-changing in solar-energy capture."

The new Dow/Caltech solar-research initiative is one of the company's largest externally funded research agreements, Banholzer notes.

As part of the agreement, Atwater, Lewis, and their team will develop new mineral-like electronic materials suitable for use in thin-film solar-energy-conversion devices. 

"Development of materials that are abundant in the earth's crust will enable solar-energy technologies to ultimately scale to large volumes at low cost without concern about the materials' availability," says Atwater.

Most solar cells today are made with silicon, which is itself an abundant material. Still, silicon solar technology has a relatively higher cost than that of current thin-film solar materials like cadmium telluride and copper indium diselenide. But these inexpensive semiconductors pose a problem of their own: they contain materials too scarce to ultimately meet the demands of full-scale solar-energy technologies.

That's why Atwater and Lewis are turning their attention to semiconductors found in the earth's crust.

"Use of earth-abundant materials can provide new technology options and could open new areas of design space," Lewis notes. "But it also brings new challenges. This project will develop the science and technology base for thin-film solar-energy conversion using these widely available materials."

"This is an example of industry stepping up to the plate with a long-term vision that acknowledges the importance of supporting research in its most fundamental forms," says Ares Rosakis, chair of the Division of Engineering and Applied Science at Caltech and Theodore von Kármán Professor of Aeronautics and Mechanical Engineering.

"Dow understands that high-quality research is occurring in both industrial and academic laboratories. We believe that partnerships like this one are crucial to our success in the development of efficient, affordable energy solutions," says Banholzer.

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Caltech Scientists Develop DNA Origami Nanoscale Breadboards for Carbon Nanotube Circuits

PASADENA, Calif.—In work that someday may lead to the development of novel types of nanoscale electronic devices, an interdisciplinary team of researchers at the California Institute of Technology (Caltech) has combined DNA's talent for self-assembly with the remarkable electronic properties of carbon nanotubes, thereby suggesting a solution to the long-standing problem of organizing carbon nanotubes into nanoscale electronic circuits.

A paper about the work appeared November 8 in the early online edition of Nature Nanotechnology

"This project is one of those great 'Where else but at Caltech?' stories," says Erik Winfree, associate professor of computer science, computation and neural systems, and bioengineering at Caltech, and one of four faculty members supervising the project.

Both the initial idea for the project and its eventual execution came from three students: Hareem T. Maune, a graduate student studying carbon nanotube physics in the laboratory of Marc Bockrath (then Caltech assistant professor of applied physics, now at the University of California, Riverside); Si-ping Han, a theorist in materials science, investigating the interactions between carbon nanotubes and DNA in the Caltech laboratory of William A. Goddard III, Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics; and Robert D. Barish, an undergraduate majoring in computer science who was working on complex DNA self-assembly in Winfree's lab.

The project began in 2005, shortly after Paul W. K. Rothemund invented his revolutionary DNA origami technique. At the time, Rothemund was a postdoctoral scholar in Winfree's laboratory; today, he is a senior research associate in bioengineering, computer science, and computation and neural systems.

Rothemund's work gave Maune, Han, and Barish the idea to use DNA origami to build carbon nanotube circuits. 

DNA origami is a type of self-assembled structure made from DNA that can be programmed to form nearly limitless shapes and patterns (such as smiley faces or maps of the Western Hemisphere or even electrical diagrams). Exploiting the sequence-recognition properties of DNA base pairing, DNA origami are created from a long single strand of viral DNA and a mixture of different short synthetic DNA strands that bind to and "staple" the viral DNA into the desired shape, typically about 100 nanometers (nm) on a side.

Single-wall carbon nanotubes are molecular tubes composed of rolled-up hexagonal mesh of carbon atoms. With diameters measuring less than 2 nm and yet with lengths of many microns, they have a reputation as some of the strongest, most heat-conductive, and most electronically interesting materials that are known. For years, researchers have been trying to harness their unique properties in nanoscale devices, but precisely arranging them into desirable geometric patterns has been a major stumbling block. 

"After hearing Paul's talk, Hareem got excited about the idea of putting nanotubes on origami," Winfree recalls. "Meanwhile, Rob had been talking to his friend Si-ping, and they independently had become excited about the same idea."

Underlying the students' excitement was the hope that DNA origami could be used as 100 nm by 100 nm molecular breadboards—construction bases for prototyping electronic circuits—on which researchers could build sophisticated devices simply by designing the sequences in the origami so that specific nanotubes would attach in preassigned positions. 

"Before talking with these students," Winfree continues, "I had zero interest in working with carbon nanotubes or applying our lab's DNA-engineering expertise toward such practical ends. But, seemingly out of nowhere, a team had self-assembled with a remarkable spectrum of skills and a lot of enthusiasm. Even Si-Ping, a consummate theorist, went into the lab to help make the idea become reality."

"This collaborative research project is evidence of how we at Caltech select the top students in science and engineering and place them in an environment where their creativity and imagination can thrive," says Ares Rosakis, chair of the Division of Engineering and Applied Science at Caltech and Theodore von Kármán Professor of Aeronautics and Professor of Mechanical Engineering.

Bringing the students' ideas to fruition wasn't easy. "Carbon nanotube chemistry is notoriously difficult and messy—the things are entirely carbon, after all, so it's extremely difficult to make a reaction happen at one chosen carbon atom and not at all the others," Winfree explains.

"This difficulty with chemically grabbing a nanotube at a well-defined 'handle' is the essence of the problem when you're trying to place nanotubes where you want them so you can build complex devices and circuits," he says.

The scientists' ingenious solution was to exploit the stickiness of single-stranded DNA to create those missing handles. It's this stickiness that unites the two strands that make up a DNA helix, through the pairing of DNA's nucleotide bases (A, T, C, and G) with those that have complementary sequences (A with T, C with G). 

"DNA is the perfect molecule for recognizing other strands of DNA, and single-stranded DNA also just happens to like sticking to carbon nanotubes," says Han, "so we mix bare nanotubes with DNA molecules in salt water, and they stick all over the nanotubes' surfaces. However, we make sure that a little bit of each DNA molecule is protected, so that that little portion doesn't stick to the nanotube, and we can use it to recognize DNA attached to the DNA origami instead."

The scientists created two batches of carbon nanotubes labeled by DNA with different sequences, which they called "red" and "blue."

"Metaphorically, we dipped one batch of nanotubes in red DNA paint, and dipped another batch of nanotubes in blue DNA paint," Winfree says. Remarkably, this DNA paint acts like color-specific Velcro.

"These DNA molecules served as handles because a pair of single-stranded DNA molecules with complementary sequences will wrap around each other to form a double helix. Thus," he says, "'red' can bind strongly to 'anti-red,' and 'blue' with 'anti-blue.'"

"Consequently," he adds, "if we draw a stripe of anti-red DNA on a surface, and pour the red-coated nanotubes over it, the nanotubes will stick on the line. But the blue-coated nanotubes won't stick, because they only stick to an anti-blue line."

To make nanometer-scale electronic circuits out of carbon nanotubes requires the ability to draw nanometer-scale stripes of DNA. Previously, this would have been an impossible task.

Rothemund's invention of DNA origami, however, made it possible.

"A standard DNA origami is a rectangle about 100 nm in size, with over 200 'pixel' positions where arbitrary DNA strands can be attached," Winfree says. To integrate the carbon nanotubes into this system, the scientists colored some of those pixels anti-red, and others anti-blue, effectively marking the positions where they wanted the color-matched nanotubes to stick. They then designed the origami so that the red-labeled nanotubes would cross perpendicular to the blue nanotubes, making what is known as a field-effect transistor (FET), one of the most basic devices for building semiconductor circuits.

Although their process is conceptually simple, the researchers had to work out many kinks, such as separating the bundles of carbon nanotubes into individual molecules and attaching the single-stranded DNA; finding the right protection for these DNA strands so they remained able to recognize their partners on the origami; and finding the right chemical conditions for self-assembly.

After about a year, the team had successfully placed crossed nanotubes on the origami; they were able to see the crossing via atomic force microscopy. These systems were removed from solution and placed on a surface, after which leads were attached to measure the device's electrical properties. When the team's simple device was wired up to electrodes, it indeed behaved like a field-effect transistor.  The "field effect" is useful because "the two components of the transistor, the channel and the gate, don't actually have to touch for there to be a switching effect," Rothemund explains. "One carbon nanotube can switch the conductivity of the other due only to the electric field that forms when a voltage is applied to it."

At this point, the researchers were confident that they had created a method that could construct a device from a mixture of nanotubes and origami.

"It worked," Winfree says. "I can't say perfectly—there's lots of room for improvement. But it was sufficient to demonstrate the controlled construction of a simple device, a cross-junction of a pair of carbon nanotubes."

"We expect that our approach can be improved and extended to reliably construct more complex circuits involving carbon nanotubes and perhaps other elements including electrodes and wiring," Goddard says, "which we anticipate will provide new ways to probe the behavior and properties of these remarkable molecules."

The real benefit of the approach, he points out, is that self-assembly doesn't just make one device at a time. "This is a scalable technology. That is, one can design the origami to construct complex logic units, and to do this for thousands or millions or billions of units that self-assemble in parallel."

The work in the paper, "Self-assembly of carbon nanotubes into two-dimensional geometries using DNA origami templates," was supported by the National Science Foundation, the Office of Naval Research, and the Center on Functional Engineered Nano Architectonics.

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Caltech and IBM Scientists Use Self-Assembled DNA Scaffolding to Build Tiny Circuit Boards

Nanotechnology advance could lead to smaller, faster, more energy-efficient computer chips

Pasadena, Calif.--Scientists at the California Institute of Technology (Caltech) and IBM's Almaden Research Center have developed a new technique to orient and position self-assembled DNA shapes and patterns--or "DNA origami"--on surfaces that are compatible with today's semiconductor manufacturing equipment. These precisely positioned DNA nanostructures, each no more than one one-thousandth the width of a human hair, can serve as scaffolds or miniature circuit boards for the precise assembly of computer-chip components.

The advance, described in the current issue of the journal Nature Nanotechnology, could allow the semiconductor industry to pack more power and speed into tiny computer chips, while making them more energy efficient and less expensive to manufacture than is possible today.  

DNA origami structures have been heralded as a potential breakthrough for the creation of nanoscale circuits and devices. In a process created by Caltech senior research associate Paul W. K. Rothemund and his colleagues, DNA molecules self-assemble in solution via a reaction between a long single strand of viral DNA and a mixture of different short synthetic DNA strands. These short segments act as staples that effectively fold the viral DNA into desired two-dimensional shapes through complementary base-pair binding.

In this way, DNA nanostructures such as squares, triangles, and stars can be prepared that measure 100 to 150 nanometers on an edge and are as thick as the DNA double helix is wide. 

One roadblock to the use of DNA origami, however, is that the structures are made in saltwater solution--whereas electronic circuits are created on surfaces, like a silicon wafer, so they can be integrated with other technologies.

DNA origami structures also adhere randomly to surfaces, which means that "if you just pour DNA origami over a surface to which they stick, they attach everywhere," explains Rothemund, who jointly led the project with IBM. "It's a little like taking a deck of playing cards and throwing it on the floor; they are scattered willy-nilly all over the place. Such random arrangements of DNA origami are not very useful. If they carry electronic circuits, for example, they are difficult to find and wire up into larger circuits."  

To eliminate these problems, Rothemund and his colleagues at the Almaden Research Center developed a way to precisely position DNA origami nanostructures on a surface, "to line them up like little ducks in a row," Rothemund says. "This knocks down one of the major roadblocks for the use of DNA origami in technology," he adds.

In a process developed by IBM scientists, electron-beam lithography and oxygen plasma etching, conventional semiconductor techniques, are used to make patterns on silicon wafers, creating lithographic templates of the proper size and shape to match those of individual triangular DNA origami structures created by Rothemund. The etched patches are negatively charged, as are DNA origami structures, and are therefore "sticky."

To connect the origami to the templates, magnesium ions are added to the saltwater solution containing the origami. The positively charged magnesium ions can stick to both the DNA origami and the negatively charged patches on the template. Thus, when the solution is poured over the template, a negative-positive-negative "sandwich" is formed, with the magnesium atoms acting as a glue to hold the origami to the sticky patches.

"The triangles bind strongly to the sticky patches, but also they can wiggle a bit, so they line up with the outline of the sticky patch. So not only can we put origami where we want them, but they can be oriented in the direction we want them," Rothemund says.

The positioned DNA nanostructures can then serve as scaffolds or miniature circuit boards for the precise assembly of components such as carbon nanotubes, nanowires, and nanoparticles at dimensions significantly smaller than possible with conventional semiconductor fabrication techniques. This opens up the possibility of creating functional devices that can be integrated into larger structures as well as enabling studies of arrays of nanostructures with known coordinates.

"The spacing between the components can be 6 nanometers, so the resolution of the process is roughly 10 times higher than the process we currently use to make computer chips," Rothemund says. "Then, if you want to design a really small electronic device, say, you just design DNA strands to create the pattern you want, attach little chemical 'fastening posts' to those DNA strands, assemble the pattern, and then assemble the components onto the pattern," he explains.

The process isn't limited to organizing things that are of interest to physical scientists and engineers, like electronic components, Rothemund adds. For example, he says, "Biologists studying how proteins interact can place them in patterns on top of DNA origami. This may be useful in the case of motor proteins, the little machines that power our muscles. They work in gangs, with multiple motors pulling together. To study how different configurations of motors cooperate, scientists may use DNA origami to organize the gangs."

"Rothemund and his colleagues have removed a key barrier to the improvement and advancement of computer chips. They accomplished this through the revolutionary approach of combining the building blocks for life with the building blocks for computing," says Ares Rosakis, Theodore von Kármán Professor of Aeronautics and Mechanical Engineering and chair of Caltech's Division of Engineering and Applied Science.

The paper, "Placement and orientation of individual DNA shapes on lithographically patterned surfaces," was published in the August 16 issue of Nature Nanotechnology. The work was supported by the National Science Foundation and the Focus Center Research Program.

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Caltech Researchers Show How Organic Carbon Compounds Emitted by Trees Affect Air Quality

Research provides first-ever glimpse of role of epoxides in atmospheric chemistry

PASADENA, Calif.—A previously unrecognized player in the process by which gases produced by trees and other plants become aerosols—microscopically small particles in the atmosphere—has been discovered by a research team led by scientists at the California Institute of Technology (Caltech).

Their research on the creation and effects of these chemicals, called epoxides, is being featured in this week's issue of the journal Science.

Paul Wennberg, the R. Stanton Avery Professor of Atmospheric Chemistry and Environmental Science and Engineering and director of the Ronald and Maxine Linde Center for Global Environmental Science at Caltech, and John Seinfeld, the Louis E. Nohl Professor and professor of chemical engineering, have been studying the role of biogenic emissions—organic carbon compounds given off by plants and trees—in the atmospheric chemical reactions that result in the creation of aerosols.

"If you mix emissions from the city with emissions from plants, they interact to alter the chemistry of the atmosphere," Wennberg notes.

While there's been plenty of attention paid to the effect of emissions from cars and manufacturing, less is understood about what happens to biogenic emissions, especially in places where there are relatively few man-made emissions. That situation is the focus of the research that led to this Science paper. "What we're interested in," Wennberg explains, "is what happens to the chemicals produced by trees once they are emitted into the atmosphere."

In these studies, the research team focused on a chemical called isoprene, which is given off by many deciduous trees. "The king emitters are oaks," Wennberg says. "And the isoprene they emit is one of the reasons that the Smoky Mountains appear smoky."

Isoprene is no minor player in atmospheric chemistry, Wennberg notes. "There is much more isoprene emitted to the atmosphere than all of the gases—gasoline, industrial chemicals—emitted by human activities, with the important exceptions of methane and carbon dioxide," he says. "And isoprene only comes from plants. They make hundreds of millions of tons of this chemical . . . for reasons that we still do not fully understand."

"Much of the emission of isoprene occurs where anthropogenic emissions are limited," adds Caltech graduate student Fabien Paulot, the paper's first author. "The chemistry is very poorly understood."

Once released into the atmosphere, isoprene gets "oxidized or chewed on" by free-radical oxidants such as OH, explains Wennberg. It is this chemistry that is the focus of this new study. In particular, the research was initiated to understand how the oxidation of isoprene can lead to formation of atmospheric particulate matter, so-called secondary organic aerosol. "A small fraction of the isoprene becomes secondary organic aerosol," Seinfeld notes, "but because isoprene emissions are so large, even this small fraction is important."

Up until now, the chemical pathways from isoprene to aerosol were not known. Wennberg, Seinfeld, and their colleagues discovered that this aerosol likely forms from chemicals known as epoxides.

The name is apt. "These epoxides are nature's glue," says Wennberg. And, much like the epoxy you buy in a hardware store—which requires the addition of an acid for the compound to turn into glue—the epoxides found in the atmosphere also need an acidic kick in order to become sticky.

"When these epoxides bump into particles that are acidic, they make glue," Wennberg explains. "The epoxides precipitate out of the atmosphere and stick to the particles, growing them and resulting in lowered visibility in the atmosphere." Because the acidity of the aerosols is generally higher in the presence of anthropogenic activities, the efficiency of converting the epoxides to aerosol is likely higher in polluted environments, illustrating yet another complex interaction between emissions from the biosphere and from humans. 

"Particles in the atmosphere have been shown to impact human health, as they are small enough to penetrate deep into the lungs of people. Also, aerosols impact Earth's climate through the scattering and absorption of solar radiation and through serving as the nuclei on which clouds form. So it is important to know where particles come from," notes Seinfeld.

The research team was able to make this scientific leap forward thanks to their development of a new type of chemical ionization mass spectrometry (CIMS), led by coauthor and Caltech graduate student John Crounse. "These new CIMS methods open up a very wide range of possibilities for the study of new sets of compounds that scientists have been largely unable to measure previously, mainly because they decompose when analyzed with traditional techniques."

In general, molecules identified and quantified using mass spectroscopy must first be converted to charged ions. They are then directed into an electric field, where the ions are sorted by mass. The problem with traditional ionization techniques is that delicate molecules, such as those produced in the oxidation of isoprene, generally fragment during the ionization process, making their identification difficult or impossible. "This new method was originally developed in order to allow scientists to make atmospheric measurements from airplanes. It is able to ionize gases, even fragile peroxide compounds, while still preserving information about the size or mass of the original molecule," says Wennberg.

That makes determining the individual gases in a complex mixture much easier—especially when, as it turned out, you're looking at a chemical you weren't expecting to find.

Wennberg and colleagues also used oxygen isotopes—oxygen atoms with different numbers of neutrons in their nucleus, and thus different masses—to gain insight into the chemical mechanism yielding epoxides. Epoxides have remained unindentified so far because they have the same mass as another chemical that had been anticipated to form in isoprene oxidation, peroxide. "The oxygen isotopes separated the peroxides from epoxides and further showed that as the epoxides form, OH is recycled to the atmosphere," comments Paulot. "Since OH is the atmosphere detergent, cleaning the atmosphere of many chemicals, the recycling has important implications for the overall oxidizing capacity of the atmosphere."

The identification of a major photochemical pathway to formation of epoxides helps to explain just how tree emissions of organic carbon compounds influence the air in both city and rural settings. While trees aren't exactly the "killers" that Ronald Reagan was once so famously derided for calling them, their isoprene emission levels can—and often probably should—"be a part of the criteria we use when buying and planting trees in a polluted urban setting," notes Wennberg. In fact, he points out, the South Coast Air Quality Management District in Southern California already does this with its list of "approved" trees that don't emit large amounts of organic carbon compounds into the atmosphere.

In addition to Wennberg, Paulot, Crounse, and Seinfeld, other authors on the Science paper, "Unexpected epoxide formation in the gas-phase photooxidation of isoprene," are Henrik Kjaergaard of the University of Otago in New Zealand and the University of Copenhagen in Denmark; former Caltech postdoctoral scholar Andreas Kürten, now at Goethe University in Germany; and Caltech postdoctoral scholar Jason St. Clair.

Purchase of the mass spectrometer used in this study was funded by a Major Research Instrumentation Award from the National Science Foundation. Additional support for the work described in the Science article came from Caltech trustee William Davidow and by grants from the Office of Science, the U.S. Department of Energy, the U.S. Environmental Protection Agency, the Royal Society of New Zealand, and NASA.

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Caltech Chemists Say Antibody Surrogates Are Just a "Click" Away

Chemists at the California Institute of Technology (Caltech) and the Scripps Research Institute have developed an innovative technique to create cheap but highly stable chemicals that have the potential to take the place of the antibodies used in many standard medical diagnostic tests.

James R. Heath, the Elizabeth W. Gilloon Professor and professor of chemistry, along with K. Barry Sharpless, the W. M. Keck Professor of Chemistry at the Scripps Research Institute and winner of the 2001 Nobel Prize in Chemistry, and their colleagues, describe the new technique in the latest issue of Angewandte Chemie, the leading European journal of chemistry.

Last year, Heath and his colleagues announced the development of the Integrated Blood-Barcode Chip, a diagnostic medical device, about the size of a microscope slide, which can separate and analyze dozens of proteins using just a pinprick of blood. The barcode chip employed antibodies, proteins utilized by the immune system to identify, bind to, and remove particular foreign compounds, such as bacteria and viruses-or other proteins.

"The thing that limits us in being able to go to, say, 200 proteins in the barcode chip is that the antibodies that you use to detect the proteins are unstable and expensive," says Heath. "We have been frustrated with antibodies for a long time, so what we wanted to be able to do was develop antibody equivalents-what we call 'protein capture agents'-that can bind to a particular protein with very high affinity and selectivity, and that pass the following test: you put a powder of them in your car trunk in August in Pasadena, and you come back a year later and they still work."

In the new work, Heath and his colleagues, including Caltech graduate student Heather D. Agnew, the first author on the Angewandte paper, have developed a protocol to quickly and cheaply make such highly stable compounds, which are composed of short chains of amino acids, or peptides. "I actually traveled to Chicago with a vial of my capture agents as airline carry-on luggage, and came back with it, and the reagent still worked," says Agnew.

The technique makes use of the "in situ click chemistry" method, introduced by Sharpless in 2001, in which chemicals are created by joining-or "clicking"-smaller subunits together.

To create a capture agent for a particular protein, the scientists devised a stepwise approach in which the first subunit of the capture agent is identified, and that unit, plus the protein, is used to identify the second subunit, and so on. For the first subunit, a fluorescent label is added to the protein, which is then incubated with a bead-based library of tens of millions of short-chain peptides, representing all the potential building blocks for the capture agent. When one of those peptides binds to the protein of interest, the fluorescent label is visualized on the bead (red, blue, or green, depending on the type of label), allowing the linked protein-peptide complex to be identified.

That first peptide-which is about a third of the length of the final capture agent the scientists are trying to make-is then isolated, purified, and modified on one end by the addition of a chemical group called an alkyne. This is the anchor peptide, which is then incubated, together with the same protein, with the bead-based library. The bead-based library now contains peptides that have been chemically modified to contain an azide group at one end. The alkyne group on the added peptide can potentially chemically react with the azide group of the library's peptides, to create a new peptide that is now two segments long.

However, the reaction can only occur when the second peptide comes into close contact with the first on the surface of the target protein, which means that both must have  affinity for that protein; essentially, the protein itself builds an appropriate capture agent. The two-segment-long peptide is then isolated and purified, "and then we modify the end of THAT with an alkyne, and add it back to the library, to produce a three-segment peptide, which is long enough to be both selective for and specific to the target protein," Heath says.

"What Heath has shown now is that in several iterations, a high-affinity ligand for a protein can be created from blocks that do not bind to the protein all that well; the trick is to repeat the in situ screen several times, and the binding improves with every iteration," Sharpless says.

"This is about as simple a type of chemistry as you can imagine," says Heath. The process, he says, makes "trivial" the "Herculean task of finding molecules that bind selectively and with high affinity to particular proteins. I see no technical reason it couldn't replace any antibody."

The paper, "Iterative in situ Click Chemistry Creates Antibody-Like Protein Capture Agents," was published in the June 22 issue of Angewandte Chemie, and highlighted in an editorial in the June issue of Nature Chemistry. The other coauthors are, at Caltech, Rosemary D. Rohde, Steven W. Millward, Arundhati Nag, Woon-Seok Yeo, Abdul Ahad Tariq, Russell J. Krom, and Vanessa M. Burns; and, at the Scripps Research Institute, Jason E. Hein, Suresh M. Pitram, and Valery V. Fokin.

The work at Caltech was funded by the National Cancer Institute and by a subcontract from the MITRE Corporation.

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Caltech Researchers Explore How Cells Reconcile Mixed Messages in Decisions About Growth

Findings have implications for tissue engineering, understanding of tumor development

PASADENA, Calif.—The cells in our body are constantly receiving mixed messages. For instance, an epithelial cell might be exposed to one signal telling it to divide and, simultaneously, another telling it to stop dividing. Understanding the process by which these competing environmental cues are reconciled—as well as understanding the cues themselves—might allow bioengineers to promote tissue growth when and where it's needed, and to discourage it when and where it's not.

The tug-of-war between these two sets of influences, and the effects they have on tissue growth, are explained and explored in a paper authored by scientists from the California Institute of Technology (Caltech) and published online in the early edition of the Proceedings of the National Academy of Sciences (PNAS). The findings in the paper may have implications for our understanding of how cancer develops, as well as for how best to grow tissues in a laboratory.

In normal epithelial tissues, mature cells that are in contact with one another tend not to divide, explains Anand Asthagiri, assistant professor of chemical engineering at Caltech, and the paper's principal investigator. This process, known as contact inhibition, is one of the ways the body keeps cell growth in check. When contact inhibition is disrupted, you get uncontrolled growth and the formation of tumors.

But what Asthagiri and colleagues have found is that contact inhibition is not a "master switch" that overrides all other environmental signals. The human body is, after all, a complex environment. And in that complex environment, contact inhibition doesn't—can't—work by itself. It is instead part of what Asthagiri calls a "tunable system," one that takes into account, and is influenced by, other signals. Among those are growth signals such as epidermal growth factor (EGF).

When Asthagiri and his colleagues studied the interplay between contact inhibition and EGF in groups of epithelial cells, they found that the cells have a threshold of sensitivity to EGF. If EGF levels dip below the threshold, contact inhibition takes hold and puts the brakes on cell division. But if EGF levels rise above the threshold, it overrides the effects of cell-cell contact and promotes cell division and tissue growth.

Both factors can potentially be manipulated—either to raise or lower the levels of growth factor or, as Asthagiri and colleagues showed in their paper, to raise or lower the contact-inhibition threshold.

In other words, Asthagiri explains, the team's research showed that it's possible to tune the system—to make cells more or less able to respond to a certain level of EGF by "playing with the extent of the contact the cells have with their neighbors."

One way to do that is to crowd the cells. "For instance," he says, "if you take a large number of cells and force them into the same area in which only a few cells are normally found, the cells become somewhat deaf to the growth factors. In order to get these cells to divide, you really have to crank up the level of growth factors they're exposed to."

You can achieve a similar result, Asthagiri adds, by creating cells that overexpress a protein called E-cadherin, which is a tumor suppressor protein that promotes adhesion of one cell to another. "This makes the cells less willing to divide," he notes, "which means they need a higher level of growth factor before they will divide."

The relationships between these competing influences "are really striking when you let them play out" under the influence of cell geography, says Asthagiri—that is, when the cells grow as a multicellular cluster. The reality is that not all cells in a cluster are exposed to the same amount of inhibition. For instance, the cells in the center of the group—pressed against other cells on all sides—will experience more contact, and will require a larger amount of growth factor if they are to overcome that inhibiting signal. The cells on the periphery of a cluster, on the other hand, get a relative whisper of an inhibitory signal; it doesn't take nearly as much growth factor to prompt those cells to divide.

Thus, it's possible to find a level of growth factor that will override the contact inhibition signal only for the peripheral cells, and then to find a second level that will allow division throughout the cluster. In other words, says Asthagiri, "You can tune the system; you can make the periphery grow more quickly relative to the rest of the area, or you can get the entire cluster to increase in size all at once."

"This is useful," he adds, "in thinking about how to engineer organs and tissues. I believe that this can become an important building block, a part of the tool set, that allows us to grow multicellular structures—and, ultimately, tissues—in specific, spatial ways."

And as for cancer? It's long been assumed that contact inhibition acts as a sort of switch that, when present, prevents tumor formation and, when absent, results in cell overgrowth and cancer. "Our findings support a more graded perspective of contact inhibition," the researchers write in the PNAS paper. Keeping in mind that cancer is often the result of an accumulation of genetic damage, they say, it seems likely that each "hit" to a cell's DNA might subtly lower the threshold at which EGF is capable of overriding contact inhibition to promote unbridled cell division and tumor growth.

"This tunability of the threshold amount of EGF," the researchers write, "would seem to be a fragility in cell cycle regulation that is exploited during cancer development."

Asthagiri's coauthors on the PNAS paper, "Tunable interplay between epidermal growth factor and cell-cell contact governs the spatial dynamics of epithelial growth," include Caltech graduate students Jin-Hong Kim, the paper's first author, and Keiichiro Kushiro, as well as former Caltech graduate student Nicholas A. Graham, who is now a postdoctoral fellow at the Crump Institute for Molecular Imaging at UCLA.

The work described was supported by the Concern Foundation for Cancer Research and the Jacobs Institute for Molecular Engineering for Medicine at Caltech.

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Lori Oliwenstein
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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.

# # #

Contact:    Lori Oliwenstein
        (626) 395-3631
        lorio@caltech.edu

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

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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.

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