Senior Caltech Nobelist Reflects on His Prize-Winning Work

It's a good thing Rudy Marcus loves libraries. Otherwise, the Noyes Professor of Chemistry at Caltech might never have stumbled across the problem that he solved to win the 1992 Nobel Prize in Chemistry.

These days, researchers can read all the leading journals online, but when Marcus was a young associate professor at the Polytechnic Institute of Brooklyn, he spent hours in the library, leafing through the chemical literature. One day in 1955, he happened across a symposium issue of the Journal of Physical Chemistry in which chemist Bill Libby laid out a theory to explain some of the puzzling observations chemists had made in the lab—namely, why some chemical reactions that involve a simple transfer of an electron happen quickly, while others take much longer to transpire.

Marcus was intrigued by Libby's explanation, which was that electrons are so light compared to the nuclei of reactants that they should be able to jump from one reactant to another before the nuclei have a chance to change. "I thought, 'That's fantastic!'" Marcus recalled recently. "Libby was taking the Franck-Condon principle—something that was devised in the 1920s for a totally different application, for interpreting the spectra of molecules—and applying it to the rate of chemical reactions." But after thinking about Libby's theory for a while, he says, "Something didn't seem quite right." That uneasy feeling launched a month-long flurry of work that yielded a different explanation—an equation and the beginnings of the Marcus theory of electron transfer that many years later won Marcus his trip to Stockholm.

Marcus realized that Libby's explanation didn't feel right because it violated the law of conservation of energy—if an electron were transferred without the nuclei changing, the system would end up with far more energy after the transfer than before. To get away from that violation, the Marcus theory says that the molecular structure of some of the nuclei of the reactant and solvent molecules have to change positions before an electron can transfer, and then adjust again afterward. Therefore, an energy barrier has to be overcome in order for an electron-transfer reaction to proceed. And since that barrier varies depending on the structure of the molecules involved, it makes sense that some reactions take longer than others. Marcus worked out a mathematical model to describe such electron-transfer reactions and to calculate the expected values for their energy barriers.

"It took one month from start to finish to produce that equation," Marcus says. "For the record, it was the fastest thing I've ever done before or since."

In addition to being completely engrossed by the problem, in many ways Marcus was prepared to attack it. Early on, as both a graduate student at McGill University, in Montreal, and as a postdoctoral fellow at the National Research Council, he had worked in the lab, measuring rates of chemical reactions. But equally critical to his success was the fact that by the time he was pondering Libby's article, Marcus had developed the ability to approach problems from a theoretical standpoint.

He hadn't always had that ability. When Marcus was in school, there were no theoretical chemists in Canada. He had taken a course in theoretical chemistry at McGill, but the professor didn't teach where the theories came from or how they were developed. So Marcus says, "It never occurred to some of us to go into theoretical chemistry." But he had always been very interested in mathematics. In fact, Marcus says he probably took more math courses at McGill than any other chemistry student at the time. So after grad school, sometime during his postdoctoral fellowship, he says, "I became very dissatisfied because I wasn't using the kind of math that I enjoyed so much." It occurred to him that theoretical chemistry might provide the blend of chemistry and mathematics he was looking for.

So he and a friend at the Research Council, Walter Trost, formed a two-man seminar. They took turns describing theoretical papers to each other and then tried to apply the findings to their own experimental work. As simple as it may sound, that preparation encouraged Marcus to take a rather bold step—to apply for a postdoctoral position in theoretical chemistry in the United States. Though Marcus had no formal training on the theoretical side, one professor, Oscar Rice from the University of North Carolina, invited the eager young chemist to join his group.

As it turned out, Marcus's decision to head to Chapel Hill was a good one for more than one reason. Within a couple weeks of his arrival, Marcus met the love of his life, Laura Hearne, a graduate student in sociology and cultural anthropology, whom he married six months later and who passed away in 2003. He was also able to nurture and develop his knowledge of theoretical chemistry. After a few months of sitting in on lectures and reading every theoretical paper he could get his hands on, and after some gentle prodding by Rice, Marcus started working on a theoretical problem that dealt with what are called unimolecular reactions. "I gradually put together the bits of a theory," Marcus says. The theory predicts how long a molecule that has acquired a lot of energy will survive in such a state before breaking up or becoming stabilized, by colliding with another molecule, for example. "Before I realized it—after being there for six months—I had developed a theory of unimolecular reactions that is still used today." That theory is referred to in textbooks as the RRKM theory—the "M" stands for Marcus.

So by the time he joined the faculty at the Polytechnic Institute of Brooklyn in 1951, Marcus had proven his theoretical chops. But sensing that there wouldn't be enough experimental results in the area of unimolecular reactions to continue on that path, he needed a new problem to focus on. Eventually, it was a student's question about electrolytes that got Marcus interested in electrostatics. He published two papers in the field before coming across Bill Libby's symposium paper in the library.

"One often hears something along the lines of, 'Discoveries come to those with a prepared mind,'" Marcus says. "Here, my preparation was that I had published something about treating electrostatic interactions. I combined that background with elements of the work I had read about that were going on in physics at the time . . . It was really a matter of putting a bunch of little ideas together."

Marcus may downplay his accomplishment, but in the Nobel award-ceremony speech, Lennart Eberson of the Royal Swedish Academy of Sciences addressed Marcus, saying, "Your theory is a unifying factor in chemistry, promoting understanding of electron-transfer reactions of biochemical, photochemical, inorganic, and organic nature and thereby contributing to science as a whole."

Marcus received his Nobel medal 19 years ago for work he started more than 35 years before that. He says that the honor changed his life in some ways—more invitations and requests came his way—but that his interest in and enthusiasm for solving problems has never waned. Today, Marcus is 88 years old and still actively working on problems in theoretical chemistry while advising postdocs and grad students.

He's also planning a return to his beloved ski slopes this winter after a couple of seasons off. In his speech at the Nobel Banquet in 1992, Marcus drew comparisons between the sport of skiing and doing theoretical work in science, offering insight into the rush he gets from both. He described "the challenge and sense of excitement when the slope is a little more difficult than one feels comfortable with."

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Kimm Fesenmaier
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Caltech Named World's Top University in New Times Higher Education Global Ranking

PASADENA, Calif.—The California Institute of Technology (Caltech) has been rated the world's number one university in the 2011–2012 Times Higher Education global ranking of the top 200 universities, displacing Harvard University from the top spot for the first time in the survey's eight-year history.

Caltech was number two in the 2010–2011 ranking; Harvard and Stanford University share the second spot in the 2011–2012 survey, while the University of Oxford and Princeton University round out the top five.

"It's gratifying to be recognized for the work we do here and the impact it has—both on our students and on the global community," says Caltech president Jean-Lou Chameau. "Today's announcement reinforces Caltech's legacy of innovation, and our unwavering dedication to giving our extraordinary people the environment and resources with which to pursue their best ideas. It's also truly gratifying to see three California schools—including my alma mater, Stanford—in the top ten."

Thirteen performance indicators representing research (worth 30% of a school's overall ranking score), teaching (30%), citations (30%), international outlook (which includes the total numbers of international students and faculty and the ratio of scholarly papers with international collaborators; 7.5%), and industry income (a measure of innovation; 2.5%) are included in the data. Among the measures included are a reputation survey of 17,500 academics; institutional, industry, and faculty research income; and an analysis of 50 million scholarly papers to determine the average number of citations per scholarly paper, a measure of research impact.

"We know that innovation is the driver of the global economy, and is especially important during times of economic volatility," says Kent Kresa, chairman of the Caltech Board of Trustees. "I am pleased that Caltech is being recognized for its leadership and impact; this just confirms what many of us have known for a long time about this extraordinary place."

"Caltech has been one of California's best-kept secrets for a long time," says Caltech trustee Narendra Gupta. "But I think the secret is out!"

Times Higher Education, which compiled the listing using data supplied by Thomson Reuters, reports that this year's methodology was refined to ensure that universities with particular strength in the arts, humanities, and social sciences are placed on a more equal footing with those with a specialty in science subjects. Caltech—described in a Times Higher Education press release as "much younger, smaller, and specialised" than Harvard—was nevertheless ranked the highest based on their metrics.

According to Phil Baty, editor of the Times Higher Education World University Rankings, "the differences at the top of the university rankings are miniscule, but Caltech just pips Harvard with marginally better scores for 'research—volume, income, and reputation,' research influence, and the income it attracts from industry. With differentials so slight, a simple factor plays a decisive role in determining rank order: money."

"Harvard reported funding increases similar in proportion to other institutions, whereas Caltech reported a steep rise (16%) in research funding and an increase in total institutional income," Baty says.

Data for the Times Higher Education's World University Rankings was provided by Thomson Reuters from its Global Institutional Profiles Project (http://science.thomsonreuters.com/globalprofilesproject/), an ongoing, multistage process to collect and validate factual data about academic institutional performance across a variety of aspects and multiple disciplines.

For a full list of the world's top 200 schools and all of the performance indicators, go to http://www.timeshighereducation.co.uk/world-university-rankings/.

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The California Institute of Technology (Caltech) is a small, private university in Pasadena that conducts instruction and research in science and engineering, with a student body of about 900 undergraduates and 1,200 graduate students. Recognized for its outstanding faculty, including several Nobel laureates, and such renowned off-campus facilities as the Jet Propulsion Laboratory, the W. M. Keck Observatory, and the Palomar Observatory, Caltech is one of the world's preeminent research centers.

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Caltech Chemist Jacqueline Barton Honored With National Medal of Science

PASADENA, Calif.—Jacqueline K. Barton, the Arthur and Marian Hanisch Memorial Professor of Chemistry and chair of the Division of Chemistry and Chemical Engineering at Caltech—a leader in studies of the chemistry of DNA—has been named one of seven recipients of the National Medal of Science, the highest honor bestowed by the United States government on scientists.

Barton was cited by the White House for her "discovery of a new property of the DNA helix, long-range electron transfer, and for showing that electron transfer depends upon stacking of the base pairs and DNA dynamics. Her experiments reveal a strategy for how DNA repair proteins locate DNA lesions and demonstrate a biological role for DNA-mediated charge transfer."

"Each of these extraordinary scientists, engineers, and inventors is guided by a passion for innovation, a fearlessness even as they explore the very frontiers of human knowledge, and a desire to make the world a better place," said President Barack Obama when announcing the awards. "Their ingenuity inspires us all to reach higher and try harder, no matter how difficult the challenges we face."

"The entire Caltech community is proud of Professor Barton," says Caltech president Jean-Lou Chameau, "and of this validation of what we've known for quite some time, which is that Professor Barton is an enormously talented scientist whose work and creativity have had a significant impact on our world and how we understand it."

Over more than 20 years, Barton has used chemistry to piece together an understanding of the way double helical DNA can behave like a wire, allowing the transfer of electrons across long molecular distances. In fundamental work, which started by attaching simple metal complexes to DNA, she showed that electrons could migrate through DNA but that the conductivity was sensitive to mistakes or lesions in the DNA.

"We thought of the base pairs of DNA something like a stack of copper pennies," Barton says, "so that if you interrupted the stack in some way—if you distorted even one penny—that would interrupt the conductivity of the stack."

Similarly, Barton has shown that even single mistakes or mismatches within the nucleic acid sequence can prevent the transfer of electrons by creating a short circuit in the DNA wire. She has used that knowledge to build new electrical sensors capable of detecting not only DNA mutations but also proteins that can bind to and distort the DNA. Recently she has formulated a model that describes how nature might use DNA electron-transfer chemistry to locate DNA lesions using specific repair proteins. 

The work has implications beyond the lab since mutations in the DNA repair machinery are associated with predispositions to diseases such as colon and breast cancer, as well as diseases associated with premature aging, such as xeroderma pigmentosum. 

"That's one of the important things about basic research," Barton says, "you never know where it's going to take you. This chemistry may be critical to DNA-based signaling across the genome to activate cellular responses to DNA damage. We started with this curious little experiment looking at simple metal complexes that did electron transfer, and now we're talking about DNA damage that results from oxidative stress and how that leads to cancer."

"Jackie's research on molecular recognition and electron transfer on the double helix of DNA has led both to fundamentally new insights into chemistry and biology and to important new sensor technology," says Ed Stolper, Caltech's provost and the William E. Leonhard Professor of Geology. "Moreover, she has been an extraordinary leader for the chemical sciences at Caltech and around the world."

Born and raised in New York City, Barton earned her AB in chemistry at Barnard College in 1974 and her PhD at Columbia University in 1978. She then carried out a postdoctoral fellowship at Bell Laboratories and Yale University. After starting her academic career at Hunter College, City University of New York, she rose through the academic ranks at Columbia University. Barton joined the Caltech faculty as a professor of chemistry in 1989 and was named the Arthur and Marian Hanisch Memorial Professor in 1997.

Barton is the recipient of numerous awards, including the 1988 American Chemical Society Award in Pure Chemistry, the 1985 NSF Waterman Award, and a MacArthur Foundation Fellowship in 1991. Barton was elected a fellow of the American Philosophical Society in 2000 and was elected to the National Academy of Sciences in 2002. She was appointed chair of the Division of Chemistry and Chemical Engineering at Caltech in 2009.

There have been 56 recipients of the medal, including Barton, who are alumni or faculty at Caltech. Barton is the first woman at Caltech to receive the National Medal of Science.

The National Science Foundation administers the National Medal of Science and its companion, the National Medal of Technology and Innovation, on behalf of the White House. Nominees are selected by a committee of Presidential appointees based on their extraordinary knowledge in and contributions to chemistry, engineering, computing, mathematics, and the biological, behavioral/social, and physical sciences.

Barton and her fellow medal recipients will receive their awards from the President at a White House ceremony later this year.

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Four Caltech Researchers Given NIH Director's Awards

Research projects will explore membrane proteins, brain activity, genetic programming, and signaling molecules

PASADENA, Calif.—Four members of the California Institute of Technology (Caltech) faculty have been named among the researchers being given National Institutes of Health (NIH) Director's Awards. The awards are administered through the NIH's Common Fund, which provides support for research deemed to be both innovative and risky.

"The NIH Director's Award programs reinvigorate the biomedical work force by providing unique opportunities to provide research that is neither incremental nor conventional," said James M. Anderson, director of the Division of Program Coordination, Planning,  and Strategic Initiatives, which guides the Common Fund's High-Risk Research program. "The awards are intended to catalyze giant leaps forward for any area of biomedical research, allowing investigators to go in entirely new directions."

There are three types of NIH Director's Awards: the Pioneer Award, the New Innovator Award, and the Transformative Research Projects Award. This year, Caltech scientists were given two of 13 Pioneer Awards; two other Caltech researchers were among the 49 scientists given New Innovator Awards.

NIH Pioneer Awards

William Clemons Jr., assistant professor of biochemistry, and Thanos Siapas, professor of computation and neural systems, were each presented with an NIH Pioneer Award to promote what the Institutes call "pioneering and possibly transforming approaches" to key challenges in biomedical and behavioral research. 

Clemons' project will focus on membrane proteins. "Membrane proteins are an abundant and important class of molecules that play critical roles in medicine," he says. "But progress in understanding these molecules has been hindered by an inability to obtain them in significant quantities. Our goal is to examine the biological principles that cause these limitations, and discover new methods to overcome them. This award will allow us to explore these ideas in ways that aren't possible through traditional funding methods." 

Clemons received his BS from Virginia Tech in 1995, and his PhD from the University of Utah in 2000, spending time at the Laboratory of Molecular Biology in Cambridge, UK. After a postdoctoral fellowship at Harvard Medical School, he arrived at Caltech in 2005.

Siapas will use his Pioneer Award to develop neural probes for large-scale recordings of brain activity. "Brain functions such as perception, learning, and memory arise from the coordinated activation of billions of neurons distributed throughout the brain," Siapas says. "While we know a lot about the properties of individual neurons, much less is known about how assemblies of neurons interact to perform computations. Our goal is to develop large-scale, multielectrode arrays that will enable the monitoring of many neurons simultaneously across different brain areas. We hope that such arrays will expose new fundamental insights into brain activity, and will find application in the study of animal models of brain disorders."

Siapas received his BS, MS, and PhD degrees from the Massachusetts Institute of Technology in 1990, 1992, and 1996, respectively. He came to Caltech in 2002, and was named a full professor in 2010.

NIH New Innovator Awards

Long Cai, assistant professor of chemistry, and Lea Goentoro, assistant professor of biology, were each given the New Innovator Award, which the NIH says is meant to both stimulate highly innovative research and support promising new investigators.

Cai and his colleagues are working to use single-molecule microscopy to help them better understand the genetic programs in individual cells. "Our idea is to label the molecules individually," says Cai. "Then we can identify where these molecules are in the cell and how many of them are there, by single-molecule counting. "

"The goal is to monitor individual cells to find out how they work," he adds. "This may provide valuable information about rogue cells that are involved in cancer and other diseases."

Cai received his BA and PhD from Harvard in 2001 and 2006, respectively, and joined the Caltech faculty in 2010.

Goentoro will be exploring the ways in which cellular signaling molecules respond to their environment. "Have you ever noticed how we can easily whisper to each other in a quiet room, but we have to shout if we're standing on a busy road?" she asks. "In perceiving the world, our sensory systems automatically change their detection sensitivity according to the ambient condition, a phenomenon known as Weber's Law. We have found evidence to suggest that each cell in our body uses this same principle in perceiving signaling molecules in its surroundings. We will use the Innovator Award to explore this relative perception in cells, the underlying mechanism, and how it goes wrong in diseases."

"I am very grateful for the award," Goentoro adds. "It will give us precious freedom to explore ideas we are very curious about."

Goentoro's BS was awarded by the University of Wisconsin, Madison, in 2001, and she got her PhD from Princeton University in 2006. She has been at Caltech since July of this year.

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Lori Oliwenstein
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Making Stem-Cell Band-Aids for the Retina

Over the coming weeks, we’ll be highlighting several undergraduates and their summer research at Caltech. Some are Techers; others hail from schools across the country. Most are participating in the Summer Undergraduate Research Fellowships (SURF) program, a unique opportunity for undergraduates to spend 10 weeks over the summer doing original research with Caltech faculty. At the end of the project, students write a paper and present their work at SURF Seminar Day, which will take place on October 15 this year.

At the beginning of July, Caltech senior Wilson Ho found himself hiking, stargazing, and camping in Yosemite National Park with a Nobel laureate. He even joined a group of scientists for a spontaneous jump into a freezing cold stream. 

Ho was spending the summer working on a SURF project in the lab of Robert Grubbs, one of the winners of the 2005 Nobel Prize in Chemistry. Therefore, he had earned himself a spot on the Grubbs team's annual camping trip.

"It feels pretty surreal sometimes," Ho says, not just of spending five days camping with Grubbs, the Victor and Elizabeth Atkins Professor of Chemistry, but also of getting the opportunity to work for the esteemed researcher. "The experience has been exactly what I was hoping for."

Ho, a chemistry major, originally contacted Grubbs in January, searching for a summer research project that dealt with catalysis or organometallic chemistry, the study of chemical compounds that contain carbon atoms bound to metals. Grubbs told him that postdoctoral scholar Paresma Patel was looking for an intern to help with a chemical-synthesis project related to macular degeneration—a disease that is associated with aging and causes cells in a part of the retina to die. Macular degeneration is estimated to affect 1.8 million Americans, with another 7.3 million at substantial risk of developing the disease. Patel's project, funded by the California Institute for Regenerative Medicine, sounded so interesting that Ho signed up.

Ho, the 2011 Rossum Family SURF Fellow, tells his nonscientist friends and family that the goal of his project is to develop "stem-cell Band-Aids." The idea is that retinal cells, derived from human embryonic stem cells (or hESC-RPE cells), would be attached to the "Band-Aids." Eventually, the strips could be surgically applied to damaged retinas, holding new cells in place long enough to be incorporated into the eye and to restore vision. 

"You might think that you could just stick stem cells in the eye and have them work," Ho says. "But it doesn't work that way because the new cells need to be held on top of the damaged tissue for some time."

What Ho is really doing is trying to coat a thin film of a bio-inert polymer called parylene with something that will encourage retinal cells to latch on. That something is a matrix containing peptides with a repeating arginine-glycine-aspartic acid amino-acid sequence, called RGD peptides.

Previous research has shown that RGD peptides bind to certain receptors expressed in hESC-RPE cells. Patel and Ho felt that the cells might bind better to a multilayered matrix containing RGD peptides, rather than just a single layer. So Ho spent much of the summer designing and carrying out a series of chemical reactions to create such a matrix.

Now that Ho has worked out how to synthesize the matrix, he's trying to figure out a way to get it to coat the parylene film. "Making one thing stick onto another that is prized for its inertness is obviously going to be a little bit difficult," Ho says with a chuckle. But he has plenty of ideas about how to try to make that happen, and he has already started testing them.

Those problem-solving skills, combined with Ho's attention to detail and his enthusiasm for the project, have impressed Patel. "Wilson surpassed the goals set out for him over the summer and will continue doing research in the Grubbs lab throughout the academic year," she says.

For his part, Ho says that he's looking forward to starting his senior year but that he truly enjoyed his SURF experience. "I love learning and being in the lab around such incredibly brilliant people—Grubbs himself, and really everyone in the lab," he says. "I've learned so much from all of them."

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Kimm Fesenmaier
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Caltech Researchers Find That Disorder Is Key to Nanotube Mystery

PASADENA, Calif.—Scientists often find strange and unexpected things when they look at materials at the nanoscale—the level of single atoms and molecules. This holds true even for the most common materials, such as water.

Case in point: In the last couple of years, researchers have observed that water spontaneously flows into extremely small tubes of graphite or graphene, called carbon nanotubes. This unexpected observation is intriguing because carbon nanotubes hold promise in the emerging fields of nanofluidics and nanofiltration, where nanotubes might be able to help maintain tiny flows or separate impurities from water. However, no one has managed to explain why, at the molecular level, a stable liquid would want to confine itself to such a small area.

Now, using a novel method to calculate the dynamics of water molecules, Caltech researchers believe they have solved the mystery. It turns out that entropy, a measurement of disorder, has been the missing key.

"It's a pretty surprising result," says William Goddard, the Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics at Caltech and director of the Materials and Process Simulation Center. "People normally focus on energy in this problem, not entropy." 

That's because water forms an extensive network of hydrogen bonds, which makes it very stable. Breaking those strong interactions requires energy. And since some bonds have to be broken in order for water to flow into small nanotubes, it would seem unlikely that water would do so freely. 

"What we found is that it's actually a trade off," Goddard says. "You lose some of that good energy stabilization from the bonding, but in the process you gain in entropy."

Entropy is one of the driving forces that determine whether a process will occur spontaneously. It represents the number of ways a system can exist in a particular state.  The more arrangements available to a system, the greater its disorder, and the higher the entropy. And in general, nature proceeds toward disorder.

When water is ideally bonded, all of the hydrogen bonds lock the molecules into place, restricting their freedom and keeping water's entropy low.  What Goddard and postdoctoral scholar Tod Pascal found is that in the case of some nanotubes, water gains enough entropy by entering the tubes to outweigh the energy losses incurred by breaking some of its hydrogen bonds. Therefore, water flows spontaneously into the tubes.

Goddard and Pascal explain their findings in a paper recently published in the Proceedings of the National Academy of Sciences (PNAS). They looked at carbon nanotubes with diameters between 0.8 and 2.7 nanometers and found three different reasons why water would flow freely into the tubes, depending on diameter.

For the smallest nanotubes—those between 0.8 and 1.0 nanometers in diameter—the tubes are so minuscule that water molecules line up nearly single file within them and take on a gaslike state.  That means the normal bonded structure of liquid water breaks down, giving the molecules greater freedom of motion. This increase in entropy draws water into the tubes.

At the next level, where the nanotubes have diameters between 1.1 and 1.2 nanometers, confined water molecules arrange themselves in stacked, icelike crystals. Goddard and Pascal found such nanotubes to be the perfect size—a kind of Goldilocks match—to accommodate crystallized water. These crystal-bonding interactions, not entropy, make it favorable for water to flow into the tubes.

On the largest scale studied—involving tubes whose diameters are still only 1.4 to 2.7 nanometers wide—the researchers found that the confined water molecules behave more like liquid water. However, once again, some of the normal hydrogen bonds are broken, so the molecules exhibit more freedom of motion within the tubes. And the gains in entropy more than compensate for the loss in hydrogen bonding energy.

Because the insides of the carbon nanotubes are far too small for researchers to examine experimentally, Goddard and Pascal studied the dynamics of the confined water molecules in simulations. Using a new method developed by Goddard's group with a supercomputer, they were able to calculate the entropy for the individual water molecules. In the past, such calculations have been difficult and extremely time-consuming. But the new approach, dubbed the two-phase thermodynamic model, has made the determination of entropy values relatively easy for any system.

"The old methods took eight years of computer processing time to arrive at the same entropies that we're now getting in 36 hours," Goddard says. 

The team also ran simulations using an alternative description of water—one where water had its usual properties of energy, density, and viscosity, but lacked its characteristic hydrogen bonding. In that case, water did not want to flow into the nanotubes, providing additional proof that water's naturally occurring low entropy due to extensive hydrogen bonding leads to it spontaneously filling carbon nanotubes when the entropy increases.

Goddard believes that carbon nanotubes could be used to design supermolecules for water purification. By incorporating pores with the same diameters as carbon nanotubes, he thinks a polymer could be made to suck water out of solution. Such a potential application points to the need for a greater understanding of water transport through carbon nanotubes.

The paper, "Entropy and the driving force for the filling of carbon nanotubes with water," appeared in the July 19 issue of PNAS. Yousung Jung of the Korea Advanced Institute of Science and Technology (KAIST) also contributed to the study. Yousung completed a postdoctoral fellowship at Caltech under Nobel Prize winner Rudy Marcus before joining the faculty at KAIST, where he and Goddard are participating in the World Class University program of Korea. They are developing practical systems as part of the Energy, Environment, Water, and Sustainability Initiative, which provided the supercomputers used in this research.

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Zewail Honored with the Royal Society's Davy Medal

Nobel Laureate Ahmed Zewail, Pauling Professor of Chemistry and professor of physics, has received the Royal Society's Davy Medal "for his seminal contributions to the study of ultrafast reactions and the understanding of transition states in chemistry, and to dynamic electron microscopy."

First awarded in 1877, the medal is named after the 19th-century British chemist and inventor Sir Humphry Davy, who was a Fellow of the Royal Society and became its president in 1820. The medal is of bronze, is accompanied by a gift of £1,000, and is awarded annually "for an outstandingly important recent discovery in any branch of chemistry." The Royal Society—of which Zewail was elected a foreign member in 2001—is the United Kingdom's independent academy for science and was founded in 1660.

A member of the U.S. National Academy of Sciences and a fellow of the American Academy of Arts and Sciences, Zewail received the Nobel Prize in Chemistry in 1999. In 2009 he was named to the President's Council of Advisors on Science and Technology, as well as 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. His many other honors include the 2011 Priestley Medal, the American Chemical Society's most prestigious award.

Zewail received his BSc from Alexandria University in 1967 and his PhD from the University of Pennsylvania in 1974. He joined Caltech's faculty in 1976 as an assistant professor, becoming professor in 1982 and Pauling Professor in 1990.

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Alternative Energy Expert Frances Arnold Profiled in the LA Times

For biochemist and chemical engineer Frances Arnold, the road to success has not been straight and narrow. In fact, she has often bucked the academic tradition of rigorous, time-consuming pre-experiment methodology for a more fast and furious approach to research.

"I said 'OK, if one experiment doesn't work I'm going to do a million experiments, and I don't care if 999,999 don't work. I'm going to find the one that does,'" said Arnold, the Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry at Caltech, in a profile published online and in the July 3 print edition of the Los Angeles Times.

Her unconventional approach has paid off. She is co-founder of a company that develops liquid fuel from plants and oversees a lab of 20 students and researchers dedicated to alternative energy.

To learn more about Arnold's career path, including a stint as a cab driver, read the full profile here

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Katie Neith
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Improving Health Assessments with a Single Cell

Caltech researchers develop quick, low-cost, and portable microchip for immune monitoring and clinical applications

PASADENA, Calif.—There's a wealth of health information hiding in the human immune system. Accessing it, however, can be very challenging, as the many and complex roles that the immune system plays can mask the critical information that is relevant to addressing specific health issues. Now, research led by scientists from the California Institute of Technology (Caltech) has shown that a new generation of microchips developed by the team can quickly and inexpensively assess immune function by examining biomarkers—proteins that can reflect the response of the immune system to disease—from single cells.

The scientists reported on their advanced technology in the May 22 online issue of Nature Medicine.

"The technology permits us for the first time to quantitatively measure the levels of many functional proteins from single, rare immune cells," says James Heath, the Elizabeth W. Gilloon Professor and professor of chemistry at Caltech and corresponding author of the study. "The functional proteins are the ones that are secreted by the cells, and they control biological processes such as cell replication and inflammation and, specific to our study, tumor killing."

In 2008, Heath—an expert in molecular electronics and personalized medicine—led the development of a "barcode chip" that, using just a pinprick's worth of blood, could measure the concentrations of dozens of proteins, including those that herald the presence of diseases like cancer and heart disease. This latest single-cell barcode chip (SCBC) device builds upon the success of that initial design, which is currently being utilized in diagnostic medical testing of certain cancer patients.

The researchers tested the chip by measuring a cancer patient's response to a type of cell-based immunotherapy designed to target and kill tumor cells. The only way to know if the therapy is doing its job is to measure many proteins at the same time from the individual cells that were targeting the tumor. The SCBC aced this test, generating readouts of a dozen secreted biomarkers—each of which represented a distinct cell function—and taking those readings from about a thousand single cells simultaneously.

The team was able to conduct a proof-of-concept study by looking at samples from a melanoma patient participating in the immunotherapy trials, and comparing those results to similar samples from three healthy subjects.

"This technology has the potential to be used routinely to monitor immune system performance," says Chao Ma, a graduate student in Heath's lab at Caltech's NanoSystems Biology Cancer Center and lead author of the Nature Medicine paper. "For example, it can be directly used to evaluate the effectiveness of certain classes of therapeutics, such as vaccines and other immunotherapies."

According to Ma, the technology is minimally invasive, cost-effective, and highly informative. The goal, he says, is to help physicians closely track the effectiveness of a therapy, and to rapidly alter or switch that therapy for the maximum benefit of the patient.

"The research fully demonstrates real-life clinical use of our revolutionary technology," Ma says.

The next step for the team will be to systematically apply the technology to clinical studies. The researchers have already begun to test the technology in additional patient populations, and to combine the SCBC with existing assays in order to get a more comprehensive picture of a therapy's efficacy.

In fact, the same study that showed the microchip's efficacy is already helping the researchers better evaluate the specific cancer immunotherapy trial, from which the patient in the study was drawn. "We are doing these same types of measurements on similar patients but at a significantly higher level of detail, and at many time points over the course of the cancer immunotherapy procedure," explains Heath. "It is helping us put together a 'movie' of the patient's immune system during the therapy, and it is providing us with some very surprising but also valuable insights into how the therapy works and how we might work with our UCLA colleagues to improve it."

"Application of this technology provides an unprecedented understanding of the human immune system by allowing an efficient and multiplexed functional readout of immune responses using limiting numbers of lymphocytes," says Antoni Ribas, associate professor of medicine and physician who led the clinical trial portion of the study at UCLA's Jonsson Comprehensive Cancer Center.

The other Caltech authors of the Nature Medicine paper, "A clinical microchip for evaluation of single immune cells reveals high functional heterogeneity in phenotypically similar T cells," are postdoctoral scholar Qihui Shi; Rong Fan, former postdoctoral scholar; former graduate students Habib Ahmad and Gabriel Kwong; and Chao-Chao Liu, former undergraduate student. Begonya Comin-Andiux, assistant professor of surgery; Thinle Chodon, assistant researcher of medicine; Richard C. Koya, assistant professor of surgery; and Caius G. Radu, associate professor of medical and molecular pharmacology from UCLA's Jonsson Comprehensive Cancer Center also contributed to the study. 

The work was funded by the National Cancer Institute, the Ivy Foundation, the Jean Perkins Foundation, the California Institute for Regenerative Medicine, the Caltech/UCLA Joint Center for Translational Medicine, the Melanoma Research Alliance, and the National Institutes of Health.

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Katie Neith
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ACS Honors Zewail

On March 29, the world's largest scientific society will bestow its highest honor on Ahmed H. Zewail, Caltech's Linus Pauling Professor of Chemistry and professor of physics. 

At its 241st National Meeting and Exposition in Anaheim, California, the American Chemical Society (ACS) will present the 2011 Priestley Medal to Zewail. The ACS, whose membership numbers over 163,000, annually awards the Priestley Medal "for distinguished services to chemistry," as stated on the back of the gold medallion. According to ACS guidelines, no individual may be so honored more than once. 

Zewail is being recognized for his pioneering work in femtochemistry, the visual study of chemical processes occurring on a scale of millionths of billionths of a second. In that period of time, light travels only about the diameter of a large virus (300 nanometers), a distance shorter even than one wavelength of visible light. 

Femtochemistry uses extremely brief flashes of laser light to illuminate molecules in motion, exposing individual images that are then stitched together in chronological order. The resulting high-resolution, slow-motion electron microscopy "movie" provides a way for scientists to view chemical processes over time, and at an unprecedented resolution.

Zewail, winner of the 1999 Nobel Prize in Chemistry, has dubbed the new science "four-dimensional (4D) electron microscopy," because it encompasses not only the standard three spatial dimensions but also the dimension of time. Applications of the technology include improved understanding of the dynamics of chemical processes, visualization of the makeup of new materials, and insights into the function of cells and other biological structures. 

The Priestley Medal commemorates the life of British scientist Joseph Priestley, who discovered oxygen in 1774 and spent the last 10 years of his life in the United States. Previous recipients include legendary Caltech chemistry professors Linus Pauling (1984), John D. Roberts (1987), and Harry B. Gray (1991).

 

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Dave Zobel
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