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State Legislators Honor Frances Arnold

Caltech chemistry professor Frances Arnold will be honored by the California Legislative Women's Caucus at its inaugural Breaking the Glass Ceiling awards ceremony in Sacramento, California, on March 4.

The ceremony, to be held in the Assembly chambers at the California State Capital, is part of the Legislative Women's Caucus commemoration of Women's History Month. Following the ceremony, Arnold and other awardees will attend a reception at the governor's office.

"I am honored to be included in the Legislative Women's Caucus's Breaking the Glass Ceiling ceremony," says Arnold. "It is important for people to know that there is a place for women in science and that female scientists are appreciated for their role in society."

Arnold will be among a small group of women so honored. According to the Legislative Women's Caucus, the Breaking the Glass Ceiling ceremony commemorates "influential women who have made an incredible contribution to California and have inspired women and girls here and beyond."

Arnold is the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry at Caltech. Her "directed evolution" research has led to the creation of biological catalysts that are useful in the production of biofuels and chemicals from renewable resources.

Arnold has won numerous awards. In December, she was named by the White House as a recipient of the 2011 National Medal of Technology and Innovation. President Barack Obama presented Arnold with her medal in a ceremony in the East Room of the White House on February 1.

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John Bercaw Wins 2012 Tolman Medal in Chemistry

The Southern California Section of the American Chemical Society (SCALACS) has selected John E. Bercaw, the Centennial Professor of Chemistry at Caltech, to receive the 2012 Tolman Medal.

According to SCALACS, the Tolman Medal honors chemists for "achievements in fundamental studies; achievements in chemical technology; significant contributions to chemical education; or outstanding leadership in science on a national level." Awardees need not be residents of Southern California, but their award-related accomplishments must have been made here.

"I am very honored to have been selected to receive the Tolman Medal," says Bercaw. "Awards such as the Tolman Medal help to inspire chemists to explore new areas of research and to help their fellow scientists."

Bercaw's research group at Caltech focuses on the development of new catalysts for producing polymers, fuels, and commodity chemicals. His group works in the area of organotransition metal chemistry and prepares new compounds, investigates their chemical reactivity, and defines the fundamental mechanisms by which they react. Bercaw's research has led to new catalysts that have been adopted by industry for producing new and improved polyethylenes, as well as to catalysts for upgrading plentiful molecules such as methane or other light hydrocarbons to produce gasoline or diesel fuel.

"As our fossil fuel resources dwindle, it is imperative that we find more efficient and greener ways to convert them into transportation fuels and materials such as plastics," says Bercaw.

Bercaw received his BS in chemistry from North Carolina State University in 1967 and a PhD in chemistry from the University of Michigan in 1971. He originally came to Caltech as an Arthur Amos Noyes Research Fellow in Chemistry in 1972. He was appointed assistant professor of chemistry in 1974, associate professor in 1977, and professor in 1979. Named Shell Distinguished Professor in 1985, then Centennial Professor in 1993, he served as executive officer for chemistry in the Division of Chemistry and Chemical Engineering from 1999 to 2002. Bercaw is a member of the National Academy of Sciences and the American Academy of Arts and Sciences.

The Tolman Medal is named in honor of Richard C. Tolman, who became professor of physical chemistry and mathematical physics at Caltech in 1921 and later dean of the graduate school. The list of previous Tolman Medal winners includes Caltech scientists Harry B. Gray, Linus C. Pauling, Jacqueline K. Barton, Ahmed Zewail, and Robert H. Grubbs.

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Visualizing Biological Networks in 4D

A unique microscope invented at Caltech captures the motion of DNA structures in space and time

PASADENA, Calif.—Every great structure, from the Empire State Building to the Golden Gate Bridge, depends on specific mechanical properties to remain strong and reliable. Rigidity—a material's stiffness—is of particular importance for maintaining the robust functionality of everything from colossal edifices to the tiniest of nanoscale structures. In biological nanostructures, like DNA networks, it has been difficult to measure this stiffness, which is essential to their properties and functions. But scientists at the California Institute of Technology (Caltech) have recently developed techniques for visualizing the behavior of biological nanostructures in both space and time, allowing them to directly measure stiffness and map its variation throughout the network.

The new method is outlined in the February 4 early edition of the Proceedings of the National Academy of Sciences (PNAS).

"This type of visualization is taking us into domains of the biological sciences that we did not explore before," says Nobel Laureate Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics at Caltech, who coauthored the paper with Ulrich Lorenz, a postdoctoral scholar in Zewail's lab. "We are providing the methodology to find out—directly—the stiffness of a biological network that has nanoscale properties."

Knowing the mechanical properties of DNA structures is crucial to building sturdy biological networks, among other applications. According to Zewail, this type of visualization of biomechanics in space and time should be applicable to the study of other biological nanomaterials, including the abnormal protein assemblies that underlie diseases like Alzheimer's and Parkinson's.

Zewail and Lorenz were able to see, for the first time, the motion of DNA nanostructures in both space and time using the four-dimensional (4D) electron microscope developed at Caltech's Physical Biology Center for Ultrafast Science and Technology. The center is directed by Zewail, who created it in 2005 to advance understanding of the fundamental physics of chemical and biological behavior.

"In nature, the behavior of matter is determined by its structure—the arrangements of its atoms in the three dimensions of space—and by how the structure changes with time, the fourth dimension," explains Zewail. "If you watch a horse gallop in slow motion, you can follow the time of the gallops, and you can see in detail what, for example, each leg is doing over time. When we get to the nanometer scale, that is a different story—we need to improve the spatial resolution to a billion times that of the horse in order to visualize what is happening."

Zewail was awarded the 1999 Nobel Prize in Chemistry for his development of femtochemistry, which uses ultrashort laser flashes to observe fundamental chemical reactions occurring at the timescale of the femtosecond (one millionth of a billionth of a second). Although femtochemistry can capture atoms and molecules in motion, giving the time dimension, it cannot concurrently show the dimensions of space, and thus the structure of the material. This is because it utilizes laser light with wavelengths that far exceed the dimension of a nanostructure, making it impossible to resolve and image nanoscale details in tiny physical structures such as DNA .

To overcome this major hurdle, the 4D electron microscope employs a stream of individual electrons that scatter off objects to produce an image. The electrons are accelerated to wavelengths of picometers, or trillionths of a meter, providing the capability for visualizing the structure in space with a resolution a thousand times higher than that of a nanostructure, and with a time resolution of femtoseconds or longer.

The experiments reported in PNAS began with a structure created by stretching DNA over a hole embedded in a thin carbon film. Using the electrons in the microscope, several DNA filaments were cut away from the carbon film so that a three-dimensional, free-standing structure was achieved under the 4D microscope.

Next, the scientists employed laser heat to excite oscillations in the DNA structure, which were imaged using the electron pulses as a function of time—the fourth dimension. By observing the frequency and amplitude of these oscillations, a direct measure of stiffness was made.

"It was surprising that we could do this with a complex network," says Zewail. "And yet by cutting and probing, we could go into a selective area of the network and find out about its behavior and properties."

Using 4D electron microscopy, Zewail's group has begun to visualize protein assemblies called amyloids, which are believed to play a role in many neurodegenerative diseases, and they are continuing their investigation of the biomechanical properties of these networks. He says that this technique has the potential for broad applications not only to biological assemblies, but also in the materials science of nanostructures.

Funding for the research outlined in the PNAS paper, "Biomechanics of DNA structures visualized by 4D electron microscopy," was provided by the National Science Foundation and the Air Force Office of Scientific Research. The Physical Biology Center for Ultrafast Science and Technology at Caltech is supported by the Gordon and Betty Moore Foundation.

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Caltech Senior Wins Churchill Scholarship

Caltech senior Andrew Meng has been selected to receive a Churchill Scholarship, which will fund his graduate studies at the University of Cambridge for the next academic year. Meng, a chemistry and physics major, was one of only 14 students nationwide who were chosen to receive the fellowship this year.

Taking full advantage of Caltech's strong tradition of undergraduate research, Meng has worked since his freshman year in the lab of Nate Lewis, the George L. Argyros Professor and professor of chemistry. Over the course of three Summer Undergraduate Research Fellowships (SURFs) and several terms in the lab, Meng has investigated various applications of silicon microwire solar cells. Lewis's group has shown that arrays of these ultrathin wires hold promise as a cost-effective way to construct solar cells that can convert light into electricity with relatively high efficiencies.

Meng, who grew up in Baton Rouge, Louisiana, first studied some of the fundamental limitations of silicon microwires in fuel-forming reactions. In these applications, it is believed that the microwires can harness energy from the sun to drive chemical reactions such as the production of hydrogen and oxygen from splitting water. Meng's work showed that the geometry of the microwires would not limit the fuel-forming reaction as some had expected.

More recently, Meng has turned his attention to using silicon microwires to generate electricity. He is developing an inexpensive electrical contact to silicon microwire chips, using a method that facilitates scale-up and can be applied to flexible solar cells.

"Andrew is one of the best undergraduates that I have had the pleasure of working with in over a decade," says Lewis. "He excels in academics, in leadership, and in research. I believe he is truly worthy of the distinction of receiving a Churchill Fellowship. " 

As he pursues a Master of Philosophy degree in chemistry at the University of Cambridge over the next year, Meng will work in the group of theoretical chemist Michiel Sprik. He plans to apply computational methods to his studies of fuel-forming reactions using solar-energy materials.

"I'm very grateful for this opportunity to learn a computational perspective, since up until now I've been doing experimental work," Meng says. "I'm very excited, and most importantly, I'd like to thank Caltech and all of my mentors and co-mentors, without whom I would not be in this position today."

According to the Winston Churchill Foundation's website, the Churchill Scholarship program "offers American citizens of exceptional ability and outstanding achievement the opportunity to pursue graduate studies in engineering, mathematics, or the sciences at Cambridge. One of the newer colleges at the University of Cambridge, Churchill College was built as the national and Commonwealth tribute to Sir Winston, who in the years after the Second World War presciently recognized the growing importance of science and technology for prosperity and security. Churchill College focuses on the sciences, engineering, and mathematics." The first Churchill Scholarships were awarded in 1963, and this year's recipients bring the total to 479 Churchill Scholars.

Each year, a select group of universities, including Caltech, is eligible to nominate students for consideration for the scholarship. Meng is the seventh Caltech student to have won the award since the year 2000. A group of Caltech faculty members and researchers work with Lauren Stolper, director of fellowships advising, to identify and nominate candidates. This year, the members of the group were Churchill Scholar alumni John Brady, the Chevron Professor of Chemical Engineering and professor of mechanical engineering; Mitchio Okumura, professor of chemical physics; Alan Cummings, senior research scientist; and Eric Rains, professor of mathematics.

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Arnold Awarded National Medal of Technology and Innovation

Frances H. Arnold, a leader in the field of protein engineering and a member of the faculty at Caltech, was one of 11 inventors to be awarded the 2011 National Medal of Technology and Innovation. President Barack Obama presented Arnold with the medal on February 1 in a ceremony in the East Room of the White House.

Watch the video from the event.

 
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Jorgensen Laboratory Awarded LEED Platinum Certification

The recent renovations of the Jorgensen Laboratory included many upgrades that were designed to reflect Caltech's commitment to sustainability. Now the building has achieved LEED Platinum certification, the highest honor of the U.S. Green Building Council.

"Achieving Platinum certification on this building was particularly rewarding given the fact that the building will serve as a studio for sustainable energy research," says John Onderdonk, director of sustainability programs at Caltech.

LEED—Leadership in Energy and Environmental Design—is a voluntary program that provides verification of green building design through a survey of prerequisites and guideline credits. To obtain LEED certification, a building must earn a minimum of 40 points on a 110-point LEED rating system scale. Jorgensen received 87 points—80 is the minimum needed for Platinum certification—for its conservation features, which include a "green" roof, natural ventilation systems, use of on-campus solar photovoltaic power, and low-flow water fixtures, among other environmentally conscious details.

Jorgensen is one of 20 LEED Platinum-certified higher-education lab buildings in the country, and one of seven in the state. It is the second higher-education lab building in the state to receive LEED Platinum certification under the current rating system. Caltech's renovation of the Linde + Robinson Lab also received LEED Platinum status last year.

The Jorgensen Lab officially opened in October 2012 and houses scientists who are focused on clean-energy research

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Friday, January 25, 2013
Annenberg 121

Course Ombudspeople Lunch

TEDxCaltech: Surmounting the Blood-Brain Barrier

This week we will be highlighting the student speakers who auditioned and were selected to give five-minute talks about their brain-related research at TEDxCaltech: The Brain, a special event that will take place on Friday, January 18, in Beckman Auditorium. 

In the spirit of ideas worth spreading, TED has created a program of local, self-organized events called TEDx. Speakers are asked to give the talk of their lives. Live video coverage of the TEDxCaltech experience will be available during the event at http://tedxcaltech.caltech.edu.

The brain needs its surroundings to be just right. That is, unlike some internal organs, such as the liver, which can process just about anything that comes its way, the brain needs to be protected and to have a chemical environment with the right balance of proteins, sugars, salts, and other metabolites. 

That fact stood out to Caltech MD/PhD candidate and TEDxCaltech speaker Devin Wiley when he was studying medicine at the Keck School of Medicine of USC. "In certain cases, one bacterium detected in the brain can be a medical emergency," he says. "So the microenvironment needs to be highly protected and regulated for the brain to function correctly."

Fortunately, a semipermeable divide, known as the blood-brain barrier, is very good at maintaining such an environment for the brain. This barricade—made up of tightly packed blood-vessel cells—is effective at precisely controlling which molecules get into and out of the brain. Because the blood-brain barrier regulates the molecular traffic into the brain, it presents a significant challenge for anyone wanting to deliver therapeutics to the brain. 

At Caltech, Wiley has been working with his advisor, Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering, to develop a work-around—a way to sneak therapeutics past the barrier and into the brain to potentially treat neurologic diseases such as Alzheimer's and Parkinson's. The scientists' strategy is to deliver large-molecule therapeutics (which are being developed by the Davis lab as well as other research groups) tucked inside nanoparticles that have proteins attached to their surface. These proteins will bind specifically to receptors on the blood-brain barrier, allowing the nanoparticles and their therapeutic cargo to be shuttled across the barrier and released into the brain.

"In essence, this is like a Trojan horse," Wiley explains. "You're tricking the blood-brain barrier into transporting drugs to the brain that normally wouldn't get in."

During his five-minute TEDxCaltech talk on Friday, January 18, Wiley will describe this approach and his efforts to design nanoparticles that can transport and release therapeutics into the brain.

For Wiley, the issue of delivering therapeutics to the brain is more than a fascinating research problem. His grandmother recently passed away from Alzheimer's disease, and his wife's grandmother also suffers from the neurodegenerative disorder.

"This is something that affects a lot of people," Wiley says. "Treatments for cardiovascular diseases, cancer, and infectious diseases are really improving. However, better treatments for brain diseases are not being discovered as quickly. So what are the issues? I want to tell the story of one of them."

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Caltech Chemical Engineer Frances Arnold Awarded National Medal of Technology and Innovation

PASADENA, Calif.—Frances H. Arnold, a leader in the field of protein engineering and a member of the faculty at the California Institute of Technology (Caltech) has been named one of 11 inventors who are the recipients of the 2011 National Medal of Technology and Innovation. The announcement was made by the White House on December 21.

Arnold, who is the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering, and Biochemistry at Caltech, pioneered methods of "directed evolution" that are now widely used to create biological catalysts for use in industrial processes, including the production of fuels and chemicals from renewable resources. In a process akin to breeding by artificial selection, directed evolution uses mutation and screening to optimize the amino-acid sequence of a protein and give it new capabilities or improve its performance. 

Arnold says her work is strongly motivated by a desire to find ways to produce fuels that can help lower carbon dioxide emissions. "I would like my children to grow up in a world that is even better than the one that I grew up in," she says. "For that to happen, we have to stop wasting precious resources and learn to live in a sustainable fashion. Biology can and should be one of the solutions."

Arnold's award brings to 13 the number of Caltech faculty members, alumni, and trustees who have received the National Medal of Technology and Innovation.

"Professor Arnold's work has led to a radical transformation in the way people understand protein engineering and what it can accomplish," says Caltech president Jean-Lou Chameau. "We are very proud of all that Professor Arnold has achieved and celebrate this recognition of her contributions." 

The National Medal of Technology and Innovation was established by Congress in 1980, and complements the older National Medal of Science. The U.S. Department of Commerce's Patent and Trademark Office administers the medal on behalf of the White House.

The White House also announced the winners of the 2011 National Medal of Science. A Caltech alumnus and former chair of the Division of Biology, Leroy Hood, was among the 12 awardees. His citation brings the number of Caltech faculty members and alumni to have received the National Medal of Science to 57.

"I am proud to honor these inspiring American innovators," said President Barack Obama in the press release. "They represent the ingenuity and imagination that has made this Nation great—and they remind us of the enormous impact a few good ideas can have when these creative qualities are unleashed in an entrepreneurial environment."

Arnold says her discoveries and accomplishments were made possible by her position at Caltech, whose structure encourages work that crosses traditional disciplinary boundaries. Indeed, her work spans chemistry, bioengineering, biochemistry, molecular biology, microbiology, and chemical engineering.

She also thanks her colleagues and students. "I'm thrilled because this is a recognition not just of my work, but of the work of many people around the world who have developed and applied these methods," Arnold says. "I've also been privileged to work with a brilliant and enthusiastic group of young people over the years."

Arnold received her undergraduate degree in mechanical and aerospace engineering at Princeton University in 1979. She became interested in protein engineering during graduate school at UC Berkeley at the beginning of the biotechnology revolution, when she realized that the then-new methods of genetic engineering offered a path to solving pressing human problems using biology.

"It was clear that being able to rewrite the code of life signified a future full of fantastic technological possibilities," she says. "I wanted to be on board."

Arnold received her PhD in 1985 and arrived at Caltech as a visiting associate in 1986. She joined the faculty as an assistant professor the following year and became associate professor in 1992, professor in 1996, and Dickinson Professor in 2000. She has been honored with many awards, including the 2011 Charles Stark Draper Prize, and holds the rare distinction of having been elected to all three branches of the National Academies—the National Academy of Engineering (2000), the Institute of Medicine (2004), and the National Academy of Sciences (2008).

"Frances has made critically important contributions through her development of directed evolution," says Jacqueline Barton, chair of the Division of Chemistry and Chemical Engineering at Caltech. "It is outstanding that this work is being recognized through the National Medal."

Arnold and her fellow medal recipients will receive their awards at a White House ceremony in early 2013. 

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Unlocking New Talents in Nature

Caltech protein engineers create new biocatalysts

PASADENA, Calif.—Protein engineers at the California Institute of Technology (Caltech) have tapped into a hidden talent of one of nature's most versatile catalysts. The enzyme cytochrome P450 is nature's premier oxidation catalyst—a protein that typically promotes reactions that add oxygen atoms to other chemicals. Now the Caltech researchers have engineered new versions of the enzyme, unlocking its ability to drive a completely different and synthetically useful reaction that does not take place in nature. 

The new biocatalysts can be used to make natural products—such as hormones, pheromones, and insecticides—as well as pharmaceutical drugs, like antibiotics, in a "greener" way.

"Using the power of protein engineering and evolution, we can convince enzymes to take what they do poorly and do it really well," says Frances Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry at Caltech and principal investigator on a paper about the enzymes that appears online in Science. "Here, we've asked a natural enzyme to catalyze a reaction that had been devised by chemists but that nature could never do."

Arnold's lab has been working for years with a bacterial cytochrome P450. In nature, enzymes in this family insert oxygen into a variety of molecules that contain either a carbon-carbon double bond or a carbon-hydrogen single bond. Most of these insertions require the formation of a highly reactive intermediate called an oxene.

Arnold and her colleagues Pedro Coelho and Eric Brustad noted that this reaction has a lot in common with another reaction that synthetic chemists came up with to create products that incorporate a cyclopropane—a chemical group containing three carbon atoms arranged in a triangle. Cyclopropanes are a necessary part of many natural-product intermediates and pharmaceuticals, but nature forms them through a complicated series of steps that no chemist would want to replicate.

"Nature has a limited chemical repertoire," Brustad says. "But as chemists, we can create conditions and use reagents and substrates that are not available to the biological world."

The cyclopropanation reaction that the synthetic chemists came up with inserts carbon using intermediates called carbenes, which have an electronic structure similar to oxenes. This reaction provides a direct route to the formation of diverse cyclopropane-containing products that would not be accessible by natural pathways. However, even this reaction is not a perfect solution because some of the solvents needed to run the reaction are toxic, and it is typically driven by catalysts based on expensive transition metals, such as copper and rhodium. Furthermore, tweaking these catalysts to predictably make specific products remains a significant challenge—one the researchers hoped nature could overcome with evolution's help.

Given the similarities between the two reaction systems—cytochrome P450's natural oxidation reactions and the synthetic chemists' cyclopropanation reaction— Arnold and her colleagues argued that it might be possible to convince the bacterial cytochrome P450 to create cyclopropane-bearing compounds through this more direct route.  Their experiments showed that the natural enzyme (cytochrome P450) could in fact catalyze the reaction, but only very poorly; it generated a low yield of products, didn't make the specific mix of products desired, and catalyzed the reaction only a few times. In comparison, transition-metal catalysts can be used hundreds of times. 

That's where protein engineering came in. Over the years, Arnold's lab has created thousands of cytochrome P450 variants by mutating the enzyme's natural sequence of amino acids, using a process called directed evolution. The researchers tested variants from their collections to see how well they catalyzed the cyclopropane-forming reaction. A handful ended up being hits, driving the reaction hundreds of times. 

Being able to catalyze a reaction is a crucial first step, but for a chemical process to be truly useful it has to generate high yields of specific products. Many chemical compounds exist in more than one form, so although the chemical formulas of various products may be identical, they might, for example, be mirror images of each other or have slightly different bonding structures, leading to dissimilar behavior. Therefore, being able to control what forms are produced and in what ratio—a quality called selectivity—is especially important.

Controlling selectivity is difficult. It is something that chemists struggle to do, while nature excels at it. That was another reason Arnold and her team wanted to investigate cytochrome P450's ability to catalyze the reaction.

"We should be able to marry the impressive repertoire of catalysts that chemists have invented with the power of nature to do highly selective chemistry under green conditions," Arnold says.

So the researchers further "evolved" enzyme variants that had worked well in the cyclopropanation reaction, to come up with a spectrum of new enzymes. And those enzymes worked—they were able to drive the reaction many times and produced many of the selectivities a chemist could desire for various substrates.  

Coelho says this work highlights the utility of synthetic chemistry in expanding nature's catalytic potential. "This field is still in its infancy," he says. "There are many more reactions out there waiting to be installed in the biological world."

The paper, "Olefin cyclopropanation via carbene insertion catalyzed by engineered cytochrome P450 enzymes," was also coauthored by Arvind Kannan, now a Churchill Scholar at Cambridge University; Brustad is now an assistant professor at the University of North Carolina at Chapel Hill. The work was supported by a grant from the U.S. Department of Energy and startup funds from UNC Chapel Hill.

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