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.

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).


Dave Zobel
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President Obama's Science Advisor to Speak on "Science, Technology and Innovation Policy"

PASADENA, Calif.—Dr. John P. Holdren, assistant to the president for science and technology, director of the White House Office of Science and Technology Policy, and co-chair of the President's Council of Advisors on Science and Technology (PCAST), will be the speaker at the 2011 DuBridge Distinguished Lecture Series at the California Institute of Technology (Caltech). The event, which is free and open to the public, will take place at 8 p.m., April 19, in Beckman Auditorium, 332 S. Michigan Ave., on the Caltech campus in Pasadena.

The title of Dr. Holdren's talk is "Science, Technology and Innovation Policy in the Obama Administration." In a question-and-answer session after his speech, Dr. Holdren will be accompanied by Nobel Laureate Dr. Ahmed Zewail, Linus Pauling Professor of Chemistry and professor of physics at Caltech. Dr. Zewail is a member of PCAST and is the U.S. Science Envoy to the Middle East. Since the January 25 revolution in Egypt, he has played a critical role in aiding the transition to a democratic state and to development in his mother country.

Prior to joining the Obama administration, Dr. Holdren was Teresa and John Heinz Professor of Environmental Policy and director of the Program on Science, Technology, and Public Policy at Harvard University's Kennedy School of Government, as well as a professor in Harvard's Department of Earth and Planetary Sciences and director of the independent, nonprofit Woods Hole Research Center.

In the early 1970s, Dr. Holdren was a member of the Caltech community as a senior research fellow in the Environmental Quality Laboratory. He later joined the faculty of UC Berkeley, where he co-led until 1996 the interdisciplinary graduate-degree program in energy and resources. Dr. Holdren holds advanced degrees in aerospace engineering and theoretical plasma physics from MIT and Stanford and is a member of the National Academy of Sciences, the National Academy of Engineering, and the American Academy of Arts and Sciences, as well as a foreign member of the Royal Society of London. Dr. Holdren served as a member of the MacArthur Foundation's board of trustees from 1991 to 2005, as chair of the National Academy of Sciences Committee on International Security and Arms Control from 1994 to 2005, and as co-chair of the independent, bipartisan National Commission on Energy Policy from 2002 to 2009.

A former president of the American Association for the Advancement of Science, Dr. Holdren's awards include a MacArthur Foundation Prize Fellowship, the John Heinz Prize in Public Policy, the Tyler Prize for Environmental Achievement, and the Volvo Environment Prize. In December 1995 he gave the acceptance lecture for the Nobel Peace Prize on behalf of the Pugwash Conferences on Science and World Affairs, an international organization of scientists and public figures in which he held leadership positions from 1982 to 1997.

The Lee A. DuBridge Distinguished Lecture series brings prominent speakers of national and international importance to the Caltech campus. The series was inaugurated in 1996 in honor of Lee A. DuBridge, president of Caltech from 1946 to 1969. DuBridge, who died in 1994, was once called America's "senior statesman of science" by Time magazine, and was considered an exemplary research-university president in an era of vast scientific, societal, and educational change. He guided the growth of the modern Caltech while maintaining an understanding and interest in national affairs that was rare among university presidents. Previous DuBridge speakers include Charles "Charlie" Munger, Warren Buffett, Walter Cronkite, John Hume, Jack Valenti, and Judy Woodruff.

No tickets are necessary for the event; at least 700 seats will be available on a first-come, first-served basis. Doors open at 7:30 p.m. For more information on the lecture, call (626) 395-4652 or, outside the greater Pasadena area, call toll free, (888) 222-5832.

Kathy Svitil
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Nobel Laureate Ahmed Zewail to be Caltech Commencement Speaker

PASADENA, Calif.—Renowned chemist and Nobel laureate Ahmed Zewail, Linus Pauling Professor of Chemistry and professor of physics at the California Institute of Technology (Caltech), will be the speaker for Caltech's 117th annual commencement ceremony, which will take place at 10 a.m. on June 10 of this year.

"Professor Zewail is an esteemed scientist and statesman," says Caltech president Jean-Lou Chameau. "Our graduates will benefit greatly from his wisdom as they prepare to enter a world where scientists and engineers are increasingly called upon to provide leadership throughout the civic arena."

Zewail received the 1999 Nobel Prize in Chemistry for his groundbreaking research that established the field of femtochemistry by enabling chemical reactions to be studied in real time, on a scale of one quadrillionth of a second. More recently, he and his group have developed four-dimensional electron microscopy for direct imaging of matter in 3-D and in time, with applications spanning physical and biological sciences.

In 2009, Zewail was appointed to President Obama's Council of Advisors on Science and Technology. That same year, he was named U.S. Science Envoy to the Middle East as part of a program created by the State Department to foster science and technology collaborations between the United States and nations throughout the Middle East, North Africa, and South and Southeast Asia. Since the January 25th revolution in Egypt, he has played a critical role in his home country's development and transition to a democratic state.

Zewail has a long-standing interest in global affairs, particularly as they relate to science, education, and world peace. His commentaries on these global issues have appeared in the International Herald Tribune, the New York Times, the Los Angeles Times, and the Wall Street Journal, among other publications. He has written more than 500 articles and books and has given public addresses all over the world.

The Caltech professor's numerous honors include the Albert Einstein World Award of Science, the Benjamin Franklin Medal, the Robert A. Welch Award in Chemistry, the Leonardo da Vinci Award, the Wolf Prize, and the King Faisal International Prize. He was awarded the Grand Collar of the Order of the Nile, Egypt's highest state honor, and was featured on postage stamps issued to honor his contributions to science and humanity. He holds honorary degrees from 40 universities around the world and is an elected member of many professional academies and societies, including the National Academy of Sciences, the American Philosophical Society, the Royal Society of London, and the Swedish, Russian, Chinese, and French Academies.

Zewail completed his early education in Egypt, receiving his Bachelor of Science and Master of Science degrees in chemistry from Alexandria University. He obtained a PhD in chemical physics from the University of Pennsylvania and, after a postdoctoral fellowship at the University of California, Berkeley, joined the faculty at Caltech in 1976.

Caltech's 2010 commencement speaker was NASA Administrator Charles Bolden.

Kathy Svitil
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Arnold Wins Draper Prize

Frances Arnold has been named co-recipient of the Charles Stark Draper Prize by the National Academy of Engineering (NAE). Arnold, Caltech's Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry, was awarded the $500,000 prize—the engineering profession's highest honor—for a method called directed evolution, used worldwide to guide the creation of certain properties in proteins and cells, allowing the engineering of novel enzymes and biocatalytic processes for pharmaceutical and chemical products.

Arnold showed that randomly mutating genes of a targeted protein, especially an enzyme, would result in some new proteins having more desirable traits than they did before the mutation. She selected the best proteins and repeated this process multiple times, essentially directing the evolution of the proteins until they had properties needed for a particular use.

The Draper Prize was given jointly to Arnold and Willem P.C. Stemmer, the CEO of Amunix.

The NAE also named Caltech alumnus Leroy Hood the recipient of the Fritz J. and Dolores H. Russ Prize—a $500,000 biennial award recognizing "a bioengineering achievement that significantly improves the human condition"—for the development of an automated DNA sequencer that "revolutionized biomedicine and forensic science," according to the prize announcement. Now the president of the Institute for Systems Biology, Hood was on the Caltech faculty when he developed the sequencer in the 1980s. 

Both prizes will be presented in Washington, D.C., on February 22.

Kathy Svitil
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Caltech/JPL Experiments Improve Accuracy of Ozone Predictions in Air-Quality Models

Team says current models may underestimate ozone levels; findings made by characterizing rates of key chemical reactions

PASADENA, Calif.—A team of scientists led by researchers from the California Institute of Technology (Caltech) and NASA's Jet Propulsion Laboratory (JPL) have fully characterized a key chemical reaction that affects the formation of pollutants in smoggy air. The findings suggest that in the most polluted parts of Los Angeles—and on the most polluted days in those areas—current models are underestimating ozone levels, by between 5 to 10 percent.

The results—published in this week's issue of the journal Science—are likely to have "a small but significant impact on the predictions of computer models used to assess air quality, regulate emissions, and estimate the health impact of air pollution, " says Mitchio Okumura, professor of chemical physics at Caltech and one of the principal investigators on the research.

“This work demonstrates how important accurate laboratory measurements are to our understanding of the atmosphere,” added JPL Senior Research Scientist Stanley P. Sander, who led that team's effort.

The key reaction in question in this research is the reaction between nitrogen dioxide, NO2, and the hydroxyl radical, OH. In the presence of sunlight, these two, along with volatile organic compounds (VOCs), play important roles in the chemical reactions that form ozone.

Until the last decade or so, it was thought that NO2 and OH combine only to make nitric acid, HONO2, a fairly stable molecule with a long lifespan in the atmosphere. "HONO2, or nitric acid, dissolves in rainwater, so that the molecules get washed away," Okumura explains. "It's basically a sink for these radicals, taking them out of the ozone equation and thus slowing down the rate of ozone formation."

Chemists had suspected, however, that a second reaction might occur as well: one that creates a compound called HOONO (pronounced WHO-no), otherwise known as peroxynitrous acid. HOONO is much less stable in the atmosphere, falling apart quickly after being created, and thus releasing the OH and NO2 back for use in the ozone-creation cycle.

But what was not known with any reasonable certainty—until now—is how fast these reactions occur, and how much HONO2 is created relative to the amount of HOONO created. Those relative amounts are known as the branching ratio, so called because OH and NO2 can chemically transform, or branch, into either HONO2 or HOONO.

Enter the Caltech and JPL teams. The JPL team took the lead on measuring the rate at which the OH + NO2 reaction produces both HONO2 and HOONO. They did this using "an advanced chemical reactor built at JPL that was designed to measure reaction rates with very high accuracy," says Sander.

Once the scientists had determined the combined reaction rate for the two possible products—coming up with rates that are on the higher rather than the lower end of the scale of previous estimates—the Caltech group took the lead to try to uncover the branching ratio, or the ratio of the rates of the two separate processes.

Using a powerful laser measurement technique called cavity ringdown spectroscopy, the team was able to detect both products being created in the lab in real time, says Okumura. "We could start the reaction and watch, within microseconds, the products being formed," he says. "That allowed us to measure the species immediately after they were formed, and before they got lost in other side reactions. That is what allowed us to figure out the branching ratio."

Because HOONO was not a well-studied molecule, another key was using state-of-the-art theoretical calculations; for this, the authors enlisted Anne McCoy, professor of chemistry at The Ohio State University. “Solving this atmospheric chemistry problem required us to use many tools from modern chemical physics,” says Okumura.

"This work was the synthesis of two very different and difficult experiments," adds Andrew Mollner, the Science paper's first author and a former Caltech graduate student who is now at the Aerospace Corporation. "While neither experiment in isolation provided definitive results, by combining the two data sets, the parameters needed for air-quality models could be precisely determined."

In the end, what they found was that the loss of OH and NO2 is slower than what was previously thought—although the reactions are fast, fewer of the radicals are going into the nitric acid sink than had been supposed, and more of it is ending up as HOONO. "This means less of the OH and NO2 go away, leading to proportionately more ozone, mostly in polluted areas," Okumura says.

Just how much more? To try to get a handle on how their results might affect predictions of ozone levels, they turned to Robert Harley, professor of environmental engineering at the University of California, Berkeley, and William Carter, a research chemist at the University of California, Riverside—both experts in atmospheric modeling—to look at the ratio's impact on predictions of ozone concentrations in various parts of Los Angeles during the summer of 2010.

The result: "In the most polluted areas of L.A.," says Okumura, "they calculated up to 10 percent more ozone production when they used the new rate for nitric acid formation."

Okumura adds that this strong effect would only occur during the times of the year when it's most polluted, not all year long. Still, he says, considering the significant health hazards ozone can have—recent research has reported that a 10 part-per-billion increase in ozone concentration may lead to a four percent increase in deaths from respiratory causes—any increase in expected ozone levels will be important to "people who regulate emissions and evaluate health risks." The precision of these results reduces the uncertainty in the models—an important step in the ongoing effort to improve the accuracy of the models used by those policymakers.

Okumura believes that this work will cause other scientists to reevaluate recommendations made to modelers as to the best parameters to use. For the team, however, the next step is to start looking at "a wider range of atmospheric conditions where this reaction may also be very important."

Sander agrees. "The present work focused on atmospheric conditions related to urban smog—i.e., relatively warm temperatures and high atmospheric pressure," he says. "But the OH + NO2 reaction is important at many other altitudes. Future work by the two groups will focus on the parts of the atmosphere affected by long-range transport of pollution by high-altitude winds (the middle and upper troposphere) and where ozone depletion from man-made substances is important (the stratosphere)."

In addition to Okumura, Sander, Mollner, McCoy, Harley, and Carter, the other authors on the Science paper, "Rate of Gas Phase Association of Hydroxyl Radical and Nitrogen Dioxide," are postdoctoral fellow Lin Feng and graduate student Matthew Sprague, both from Caltech; former JPL postdoctoral researchers Sivakumaran Valluvadasan, William Bloss, and Daniel Milligan; and postdoctoral fellow Philip Martien from the University of California, Berkeley.

Their work was supported by grants from NASA, the California Air Resources Board, and the National Science Foundation, and by a NASA Earth Systems Science Fellowship and a Department of Defense National Defense Science and Engineering Graduate Fellowship.

JPL is a federally funded research and development facility managed by Caltech for NASA.

Lori Oliwenstein

NIH Awards $11.5 Million for New Caltech-Led Membrane-Protein Center

PASADENA, Calif.—The National Institutes of Health (NIH) has awarded $11.5 million to a consortium of research institutions led by the California Institute of Technology (Caltech) for the creation of a center for the study of membrane-protein structures.

The center—called the Center for the X-ray Structure Determination of Human Transporters—is one of nine new membrane-protein centers established by the NIH to "solve the structures of these elusive yet very medically relevant proteins," says Ward Smith, director of the NIH's Protein Structure Initiative (PSI), which is supporting the Caltech-led center. "This center brings together a powerhouse of investigators who, working in collaboration, will shed new light on the basic biology of these important membrane proteins and their potential role in treating disease."

"All cells are surrounded by membranes," says Doug Rees, the Roscoe Gilkey Dickinson Professor of Chemistry at Caltech and a Howard Hughes Medical Institute investigator,

who has been named principal investigator for the new center. "The cell membrane serves as a permeability barrier that regulates the flow of matter, information, and energy between the inside of the cell and the external environment. Transporters are specialized membrane proteins that mediate the passage of virtually every molecule in and out of cells."

These membrane proteins are "really important, biologically," he adds. "Twenty-five percent of all proteins encoded in the human genome are membrane proteins, and over half of all drugs work on membrane proteins. Transporters are vital to the biology of all cells, and a variety of diseases occur when these processes are disrupted, as in several genetic disorders or the up-regulation of multidrug resistance transporters by tumor cells." 

Specifically, Rees and his new center will be focusing on membrane transporter proteins; scientists have identified 521 of these specialty proteins in humans. The team's goal, he says, is to "try to determine the structures of as many as we can to help understand how transporters function as molecular pumps moving molecules across membranes."

Putting together a detailed structural picture of a protein is no easy task; Rees says that finding the structure of a single such protein normally takes the same amount of time—five years—as the period over which the center is being funded.

But by working to "come up with an efficient pipeline for streamlining the protein- structure determination process," Rees says, their hope is that they will be able to increase the rate of discovery by at least an order of magnitude. "It's an entirely different approach," he adds. "In the end, we're hoping to find 10 or 15 structures."

The point of all this effort, Rees says, is to "connect a protein's structure with how it functions in a biological system." This structure-based approach to biological function was pioneered at Caltech by Linus Pauling starting in the 1940s, Rees adds, and has guided most subsequent advances in understanding the molecular mechanisms of biological systems.

In other words, to really understand how a protein works, you have to know what it looks like. "And that information," Rees says, "is really important in designing therapeutics that target the protein."

In creating and running the center, Rees will be collaborating with William Clemons Jr., assistant professor of biochemistry at Caltech, as well as with two former Caltech researchers: Geoffrey Chang of the Scripps Research Institute, who was a postdoc in Rees's laboratory, and Michael Stowell of the University of Colorado, who received his PhD in chemistry at Caltech. Researchers from the Sanford-Burnham Medical Research Institute, UC San Diego, Stanford University, and Texas Tech will add their expertise.

The PSI started in 2000 with the main goal of developing highly efficient, or high-throughput, methods for revealing the structures of many different proteins. The Center for the X-ray Structure Determination of Human Transporters is part of the PSI's third phase, PSI:Biology. For the complete list of awards, see the PSI:Biology Network page at

Lori Oliwenstein
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Caltech Researchers Design a New Nanomesh Material

Silicon-based film may lead to efficient thermoelectric devices

PASADENA, Calif.—Computers, light bulbs, and even people generate heat—energy that ends up being wasted. With a thermoelectric device, which converts heat to electricity and vice versa, you can harness that otherwise wasted energy. Thermoelectric devices are touted for use in new and efficient refrigerators, and other cooling or heating machines. But present-day designs are not efficient enough for widespread commercial use or are made from rare materials that are expensive and harmful to the environment.

Researchers at the California Institute of Technology (Caltech) have developed a new type of material—made out of silicon, the second most abundant element in Earth's crust—that could lead to more efficient thermoelectric devices. The material—a type of nanomesh—is composed of a thin film with a grid-like arrangement of tiny holes. This unique design makes it difficult for heat to travel through the material, lowering its thermal conductivity to near silicon's theoretical limit. At the same time, the design allows electricity to flow as well as it does in unmodified silicon.

"In terms of controlling thermal conductivity, these are pretty sophisticated devices," says James Heath, the Elizabeth W. Gilloon Professor and professor of chemistry at Caltech, who led the work. A paper about the research will be published in the October issue of the journal Nature Nanotechnology.

A major strategy for making thermoelectric materials energy efficient is to lower the thermal conductivity without affecting the electrical conductivity, which is how well electricity can travel through the substance. Heath and his colleagues had previously accomplished this using silicon nanowires—wires of silicon that are 10 to 100 times narrower than those currently used in computer microchips. The nanowires work by impeding heat while allowing electrons to flow freely.

In any material, heat travels via phonons—quantized packets of vibration that are akin to photons, which are themselves quantized packets of light waves. As phonons zip along the material, they deliver heat from one point to another. Nanowires, because of their tiny sizes, have a lot of surface area relative to their volume. And since phonons scatter off surfaces and interfaces, it is harder for them to make it through a nanowire without bouncing astray. As a result, a nanowire resists heat flow but remains electrically conductive.

But creating narrower and narrower nanowires is effective only up to a point. If the nanowire is too small, it will have so much relative surface area that even electrons will scatter, causing the electrical conductivity to plummet and negating the thermoelectric benefits of phonon scattering.

To get around this problem, the Caltech team built a nanomesh material from a 22-nanometer-thick sheet of silicon. (One nanometer is a billionth of a meter.) The silicon sheet is converted into a mesh—similar to a tiny window screen—with a highly regular array of 11- or 16-nanometer-wide holes that are spaced just 34 nanometers apart.

Instead of scattering the phonons traveling through it, the nanomesh changes the way those phonons behave, essentially slowing them down. The properties of a particular material determine how fast phonons can go, and it turns out that—in silicon at least—the mesh structure lowers this speed limit. As far as the phonons are concerned, the nanomesh is no longer silicon at all. "The nanomesh no longer behaves in ways typical of silicon," says Slobodan Mitrovic, a postdoctoral scholar in chemistry at Caltech. Mitrovic and Caltech graduate student Jen-Kan Yu are the first authors on the Nature Nanotechnology paper.

When the researchers compared the nanomesh to the nanowires, they found that—despite having a much higher surface-area-to-volume ratio—the nanowires were still twice as thermally conductive as the nanomesh. The researchers suggest that the decrease in thermal conductivity seen in the nanomesh is indeed caused by the slowing down of phonons, and not by phonons scattering off the mesh's surface. The team also compared the nanomesh to a thin film and to a grid-like sheet of silicon with features roughly 100 times larger than the nanomesh; both the film and the grid had thermal conductivities about 10 times higher than that of the nanomesh.

Although the electrical conductivity of the nanomesh remained comparable to regular, bulk silicon, its thermal conductivity was reduced to near the theoretical lower limit for silicon. And the researchers say they can lower it even further. "Now that we've showed that we can slow the phonons down," Heath says, "who's to say we can't slow them down a lot more?"

The other authors on the paper, "Reduction of thermal conductivity in phononic nanomesh structures," are Caltech graduate students Douglas Tham and Joseph Varghese. The research was funded by the Department of Energy, the Intel Foundation, a Scholar Award from the King Abdullah University of Science and Technology, and the National Science Foundation.

Marcus Woo
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Caltech Chemists Develop Simple Technique to Visualize Atomic-Scale Structures

PASADENA, Calif.—Researchers at the California Institute of Technology (Caltech) have devised a new technique—using a sheet of carbon just one atom thick—to visualize the structure of molecules. The technique, which was used to obtain the first direct images of how water coats surfaces at room temperature, can also be used to image a potentially unlimited number of other molecules, including antibodies and other biomolecules.

A paper describing the method and the studies of water layers appears in the September 3 issue of the journal Science.

"Almost all surfaces have a coating of water on them," says James Heath, the Elizabeth W. Gilloon Professor and professor of chemistry at Caltech, "and that water dominates interfacial properties"—properties that affect the wear and tear on that surface. While surface coatings of water are ubiquitous, they are also very tough to study, because the water molecules are "in constant flux, and don't sit still long enough to allow measurements," he says.

Quite by accident, Heath and his colleagues developed a technique to pin down the moving molecules, under room-temperature conditions. "It was a happy accident—one that we were smart enough to recognize the significance of," he says. "We were studying graphene on an atomically flat surface of mica and found some nanoscale island-shaped structures trapped between the graphene and the mica that we didn't expect to see."

Graphene, which is composed of a one-atom-thick layer of carbon atoms in a honeycomb-like lattice (like chicken wire, but on an atomic scale), should be completely flat when layered onto an atomically flat surface. Heath and his colleagues—former Caltech graduate student Ke Xu, now at Harvard University, and graduate student Peigen Cao—thought the anomalies might be water, captured and trapped under the graphene; water molecules, after all, are everywhere.

To test the idea, the researchers conducted other experiments in which they deposited the graphene sheets at varying humidity levels. The odd structures became more prevalent at higher humidity, and disappeared under completely dry conditions, leading the researchers to conclude that they indeed were water molecules blanketed by the graphene. Heath and his colleagues realized that the graphene sheet was "atomically conformal"—it hugged the water molecules so tightly, almost like shrink wrap, that it revealed their detailed atomic structure when examined with atomic force microscopy. (Atomic force microscopes use a mechanical probe to essentially "feel" the surfaces of objects.)

"The technique is dead simple—it's kind of remarkable that it works," Heath says. The method, he explains, "is sort of like how people sputter carbon or gold onto biological cells so they can image them. The carbon or gold fixes the cells. Here, the graphene perfectly templates the weakly adsorbed water molecules on the surface and holds them in place, for up to a couple of months at least."

Using the technique, the researchers revealed new details about how water coats surfaces. They found that the first layer of water on mica is actually two water molecules thick, and has the structure of ice. Once that layer is fully formed, a second, two-molecule-thick layer of ice forms. On top of that, "you get droplets," Heath says. "It's truly amazing that the first two adsorbed layers of water form ice-like microscopic islands at room temperature," says Xu. "These fascinating structures are likely important in determining the surface properties of solids, including, for example, lubrication, adhesion, and corrosion."

The researchers have since successfully tested other molecules on other types of atomically flat surfaces—such flatness is necessary so the molecules don't nestle into imperfections in the surface, distorting their structure as measured through the graphene layer. "We have yet to find a system for which this doesn't work," says Heath. He and his colleagues are now working to improve the resolution of the technique so that it could be used to image the atomic structure of biomolecules like antibodies and other proteins. "We have previously observed individual atoms in graphene using the scanning tunneling microscope," says Cao. "Similar resolution should also be attainable for graphene-covered molecules."

"We could drape graphene over biological molecules—including molecules in at least partially aqueous environments, because you can have water present—and potentially get their 3-D structure," Heath says. It may even be possible to determine the structure of complicated molecules, like protein–protein complexes, "that are very difficult to crystallize," he says.

Whereas the data from one molecule might reveal the gross structure, data from 10 will reveal finer features—and computationally assembling the data from 1,000 identical molecules might reveal every atomic nook and cranny.

If you imagine that graphene draped over a molecule is sort of like a sheet thrown over a sleeping cat on your bed, Heath explains, having one image of the sheet-covered lump—in one orientation—"will tell you that it's a small animal, not a shoe. With 10 images, you can tell it's a cat and not a rabbit. With many more images, you'll know if it's a fluffy cat—although you won't ever see the tabby stripes."

The work in the paper, "Graphene Visualizes the First Water Adlayers on Mica at Ambient Conditions," was funded by the United States Department of Energy's Office of Basic Energy Sciences.

Kathy Svitil

"The Impact That Our Students Have on the World Is Remarkable"

A Q&A with Chemistry and Chemical Engineering Chair Jacqueline Barton

As a chemist, Jacqueline Barton appreciates the importance of bonds—between atoms to make molecules, of course, but also bonds forged between people, scientists, and scientific disciplines, all of which apply to Caltech's Division of Chemistry and Chemical Engineering (CCE), which she currently chairs. In that multifaceted interdisciplinary environment, says Barton, where cutting-edge research is under way on dozens of fronts, the strongest bonds are those created by graduate students—more than 300 of them, working with faculty and fellow students on research ranging from investigations into the molecular basis of disease to the quest for abundant clean energy. "Our graduate students are the lifeblood of the division," says Barton, "the essence of what we do."

That's why the Hanisch Memorial Professor and professor of chemistry has launched an ambitious, unprecedented campaign to raise $30 million to create 40 endowed graduate-student fellowships. "Competition for the top graduate students is keen," says Barton. "It's absolutely essential that we establish this permanent fellowship program if we are to continue to be the best."

In this Q&A Barton talks about the division and its graduate students, past, present—and future.

Why have you put such a high priority on raising new funds for graduate student fellowships?

Let me start with a little history. This is a truly outstanding division. Linus Pauling, one of our earliest division chairs, worked for 20 years in the office where we're sitting now. And the people who worked with him and who came after him have been extraordinary. On our own faculty, we currently have the largest number of Nobel laureates in a department of chemistry in the world, as well as faculty who have received the National Medal of Science.  

What's most impressive, and makes us all, I think, the most proud, is the quality of the students whom we train and the contributions that they go on to make through their own careers. If you look at the faculty at the top chemistry or chemical engineering departments in this country, you will find that an amazing number of them have spent time at Caltech, either as PhD students, undergrads, or postdocs. We are training the best and the brightest, who are now leaders in academia and industry across the country. The impact that our students have on the world after leaving Caltech is remarkable, particularly when you think about how small an institution we are.

So it's not surprising that our chemistry program is ranked first in the nation—and my job is to keep it that way.  And what makes us what we are and who we are, is, most importantly, our graduate students. They make the place run, and, quite frankly, they run the place.

What do an endangered sea slug and cancer patients have in common? A compound produced by the first may one day treat the second. In the lab of Professor Brian Stoltz, grad students Allen Hong, Nathan Bennett, and (in the back) Chris Gilmore are creating synthetic replicas of medicinal substances produced by plants and animals, some of them rare or endangered. This research could ultimately lead to large-scale production of potent new disease-fighting drugs.
Credit: Mike Rogers

They run the place?

They absolutely run the place. I think that's why we're so good. Our students are the heart of our division, they are at the heart of our research, they are an indispensable part of everything that we do. And our greatest challenge is to provide consistent support for them. That's a more complicated proposition than it once was, when we could count on more sustained federal funding. These days, funding goes up and funding goes down, but when you make a commitment to a student working toward his or her PhD, that's generally a five-year commitment.

What are some of the research areas that these students work in?  What key questions are they investigating?

Today, probably half of the division works on problems that are related to biological questions—questions at the biomedical frontiers. In the past 10 to 20 years, science has come up with the tools and techniques to ask biological questions at the molecular level—and that's chemistry. Chemists now have the unprecedented ability to probe biological systems at the fundamental level of molecules and their interactions, and our graduate students are an incredibly vital part of this research. They're looking at different aspects of biological signaling—how information is exchanged—in every important biological system, from nerve cells, to the genome, to the immune system. That information is chemical.  Whether it's finding innovative methods of drug delivery or engineering new proteins and new molecules to carry out new kinds of chemical reactions, that work is very much at the heart of what we do. Their research is leading to the development of new drugs and new diagnostic agents for a whole range of applications in medicine.

Another major research area, one that's of crucial importance not just to our nation but to the whole planet, is how we come up with alternative energy sources. That, too, is a problem in chemistry, and the solution requires chemical engineering. We have graduate students collaborating closely with faculty on ways to develop new methods for harnessing energy from the sun and converting it into clean fuels on a large scale. They'll be very much involved in all aspects of the work that goes on in the DOE's new Joint Center for Artificial Photosynthesis—which will be headquartered on the Caltech campus—and Caltech's Resnick Sustainability Institute, both of which will be working to develop novel and viable approaches to renewable energy technologies. We expect extraordinary things to come out of these programs.

Damage to cellular DNA lies at the root of many serious disorders, including cancer. From left, graduate students Pam Sontz, Anna Nordstrom, and Eric Olmon working in Professor Jackie Barton's lab, are conducting fundamental research into how specific proteins in the body recognize and initiate repairs to damaged DNA, and what causes this maintenance system to go awry. This work is shedding light on the origins of numerous diseases and could lead to the development of powerful new treatments.
Credit: Mike Rogers

So, as you can see, work in our division is very varied and highly interdisciplinary. Chemists like to say that chemistry is the central discipline, and that's never been more true than it is today, as we push the boundaries toward physics, toward biology, and use our discoveries to engineer new materials, new medicines, and new devices. And if you want to pursue and maintain a thriving interdisciplinary program, you need a critical mass of people who are working in all these different areas, exchanging information, and sharing new ideas and perspectives. For us, in large part, that's our graduate students. They are the glue that binds this cohesive effort together.

So, we have to preserve this treasure at the heart of our chemistry community—and that means taking care of our graduate students.

Can you talk about some of the exceptional people who received their PhDs from this division?

Sure. I like to start with Gordon Moore—everyone knows his name, but plenty of people are surprised to hear that he earned his Caltech PhD in physical chemistry. He cofounded Intel, he propounded Moore's Law, and he and his wife, Betty, have created one of this country's great philanthropic foundations, which supports all kinds of initiatives in education and the environment. Certainly, our world would be quite different without him.

Another Caltech chemist renowned as an innovator, industrialist, and philanthropist is, of course, Arnold Beckman. He started with the pH meter and went on to invent revolutionary instruments that led to new discoveries in biochemistry and medicine. He founded Beckman Instruments, and also established a foundation that has provided magnificent support for higher education. There's William Lipscomb, who studied here with Linus Pauling in the 1940s. He won the Nobel Prize in 1976 for his fundamental work on chemical bonding.

George Whitesides, who's been a professor at Harvard for many years, got his PhD here in 1964, and if you were to ask, what has he done, I would have to answer, What hasn't he done? He helped to move forward the field of nanoscience with his studies of how molecules arrange themselves on surfaces. He's opened whole new areas of research in developing innovative new tools and principles for surface science, molecular self-assembly, and nanotechnology. Students of his have come to Caltech as graduate students or postdocs, and vice versa, so he's also an excellent example of the cross-fertilization that we have going on with successive generations of graduate students.

We have alumni from this division who have become leaders in biotechnology, like Michael Hunkapiller, who for many years was president of the company Applied Biosystems. Richard Scheller is another. He's now the VP for Research at Genentech, and just this spring he shared the $1 million Kavli Prize in Neuroscience. The prize was for work that he did as a professor at Yale on how nerve cells communicate through molecular signaling, and it has its roots in research he began here at Caltech as a grad student in chemistry.

Other graduates have gone on to become major players in academic administration—for instance, Mark Wrighton, who spent five years as provost of MIT and has now been chancellor of Washington University in St. Louis for 15 years. This just gives you a sense of how productive our former students have been, and in so many different areas. 

What about more recent graduates?

We have so many of them working in exciting areas. I'll just mention a few who have graduated in the last decade or so. Justin Gallivan, who's now at Emory University in Atlanta, heads up a research group that is interested in reprogramming molecules like those in the bacterium E. coli, so that they can carry out tasks like environmental cleanup and energy conversion. At Harvard, another of our graduates, Ted Betley, is developing assemblies of molecules that mimic the action of plants in using sunlight to split water into oxygen and hydrogen to produce clean, cheap energy. In 2008, he was named one of the nation's leading young innovators by Technology Review.

The recruitment of gifted graduate students is indispensable to the future of chemistry and chemical engineering, says Caltech's Jackie Barton.
Credit: Bob Paz

And now so many of our outstanding graduate-student alumni are women—scientists like Melanie Sanford at the University of Michigan, who is also pioneering new approaches to green chemistry, making remarkably efficient catalysts for organic synthesis. One of my own former PhD students, Sarah Delaney, heads up a team at Brown that's investigating how different types of DNA damage are implicated in cancer and incurable inherited conditions like Huntington's disease.

These are all ambitious projects with incredible potential. The scientists who are working on them are precisely the kind of outstanding young people whom Caltech must continue to attract and to educate. That's why this fellowship support is so essential.

Let's take an "It's a Wonderful Life" approach for a moment, and imagine a CCE division at Caltech that has fewer graduate students because they didn't have access to these fellowships. What would happen?

We wouldn't be the best anymore. We wouldn't be able to attract the exceptional faculty that we do. We would lose our ability to attract the very best scientists in the world—from graduate students to senior professors—to come here and do science together. When you are the best, you can never take that status for granted—you have to work hard to stay that way. The outstanding science that we do here is rooted in our ability to gather together the remarkable people that we have. Caltech is an extraordinarily collaborative, interactive place, and that's how the best science comes to be.

Heidi Aspaturian
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