Two Caltech Scientists Named Among 2010 NIH Director's New Innovator Awardees

PASADENA, Calif.—As part of a National Institutes of Health (NIH) initiative to stimulate highly innovative research and support promising new scientific investigators, two scientists from the California Institute of Technology (Caltech) were named among the 2010 class of the NIH Director's New Innovator Award recipients.

Alexei Aravin, assistant professor of biology, and Changhuei Yang, associate professor of electrical engineering and bioengineering, were among those honored with the grants, which are meant to help new investigators take exceptional and innovative research ideas to the next level.

"NIH is pleased to be supporting early-stage investigators from across the country who are taking considered risks in a wide range of areas in order to accelerate research," says Francis S. Collins, director of the National Institutes of Health. "We look forward to the results of their work."

Yang and his research team will be pushing in a new research direction in biophotonics—the study of the interaction of time-reversed light with biological structures. When light hits the body's tissues, the light scatters, making visualizing structures under the skin extremely difficult. "A couple of years ago, my group experimentally demonstrated that it is possible to reduce tissue opacity"—make the tissues and their structures easier to see—"by time-reversing tissue light transmission," Yang explains. Put simply, they traced the paths of the scattered photons back through the tissues, showing that, by doing so, they could create images of what the light had encountered on its way in.

"We believe that this phenomenon holds a key to deep-tissue optical imaging and therapy," says Yang. "I am grateful for this New Innovator award, because it will allow my group to better understand the science and develop technologies that can capitalize on its advantages. If our work pans out well, it could lead the way to deep-tissue surgery without incision points, highly targeted optical-based cancer therapies, ultrasound imaging with chemical specificity, and better microscopy."

Yang received his BS, MS, and PhD from the Massachusetts Institute of Technology. He joined Caltech as an assistant professor of electrical engineering in 2003, became assistant professor of electrical engineering and bioengineering in 2004, and was named associate professor in 2009.

The research for which Aravin was singled out focuses on understanding the functions of small RNA—tiny snippets of ribonucleic acid that play a role in silencing genes through a pathway known as RNA interference. A few years ago, Aravin discovered a new class of small RNA that provides protection against a type of genomic parasite—the so-called transposable elements. He will use the New Innovator award to study the ways in which "small-RNA pathways can be programmed to modulate gene expression and cause heritable phenotypic changes"—changes to the proteins a cell makes, as well as to its other traits and characteristics. His goal? To use small RNA to develop tools and methodologies that can actively direct a cell down a particular developmental pathway.

"Achievement of these goals will be of great importance for both general science and medicine," says Aravin, "as it will provide insights into processes of development and lineage commitment and allow major advances to be made in medical applications such as stem cell technologies and anticancer therapies."

Aravin received his BS, MSc, and PhD from Moscow State University and joined the Caltech faculty in 2009.

Lori Oliwenstein
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Jerrold E. Marsden, 68

Jerrold Eldon Marsden, the Carl F. Braun Professor of Engineering, Control and Dynamical Systems, and Applied and Computational Mathematics at Caltech, passed away on the evening of September 21, 2010, with his wife and daughter by his side. He was 68.

Marsden was one of the leading world experts in mathematical and theoretical mechanics. His work spanned a variety of fields, including fluid mechanics, geometric mechanics, elasticity, control theory, dynamical systems, and numerical methods. By focusing on geometric foundations, he was able to unite different disciplines, connecting mathematical theory with physical models and practical applications. His work has, consequently, influenced geometers and physicists alike. His research has led to advances in many areas, including spacecraft mission design, turbulence modeling, and the design of underwater vehicles. Marsden's influence was felt around the globe, in no small part because of his countless international collaborations.

"Jerry was an amazing intellectual, a gifted professor, and one of the finest colleagues that I have met," says Ares Rosakis, the Theodore von Kármán Professor of Aeronautics and professor of mechanical engineering, and chair of the Division of Engineering and Applied Science. "He was a great mentor to many of our Caltech students and our younger colleagues."

Born in Ocean Falls, British Columbia, Canada, Marsden graduated from the University of Toronto in 1965 with a BSc in mathematics. He received his PhD in applied mathematics in 1968 from Princeton University. He then joined the faculty at the University of California, Berkeley, before coming to Caltech in 1992 as a Fairchild Distinguished Scholar. He was appointed professor of control and dynamical systems in 1995, and in 2003, he was named the Carl F. Braun Professor. In 1992, he helped found the Fields Institute, a mathematical research institute at the University of Toronto, where he was a director until 1994.

Marsden was an accomplished educator and mentor, having written six undergraduate math textbooks, which are used worldwide, and 14 monographs, many of which are the definitive references in their fields. He has had more than 40 PhD students and postdocs. In 2006, Caltech's Graduate Student Council awarded him its Teaching and Mentoring Award.

He received numerous other awards that recognized his contributions as a researcher and educator: the Jeffrey-Williams Prize, the AMS-SIAM Norbert Wiener Prize, two Humboldt Prizes, a Fairchild Fellowship, the Max Planck Research Award, the SIAM von Neumann Prize, and the United Technologies Research Award. In 2006, he received an honorary doctorate from the University of Surrey. He will posthumously be awarded the 2010 Thomas K. Caughey Award this coming November in Vancouver.

He was elected a fellow of the Royal Society in 2006 and was a fellow of the Royal Society of Canada and the American Academy of Arts and Sciences.

He is survived by his wife, Barbara; his children, Christopher and Alison; grandchildren Eliza and Isaac; and sister Judy.

The family has requested that, in lieu of flowers, contributions be made to the Jerrold E. Marsden Scholarship Fund, which is an endowment that will be used to support students in Caltech's Department of Computing and Mathematical Sciences. Alternatively, contributions can be made to the Pasadena dog rescue, Mutts and Moms.

Jon Weiner
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Caltech Engineer Named MacArthur Fellow

PASADENA, Calif.—John O. Dabiri, a fluid-dynamics expert at the California Institute of Technology (Caltech) whose studies of schooling fish have inspired new ideas for wind farming, was named a MacArthur Fellow today, and awarded a five-year, $500,000 "no strings attached" grant. Each year, the John D. and Catherine T. MacArthur Foundation awards the unrestricted fellowships—also known as "genius" grants—to individuals who show "exceptional creativity in their work and the prospect for still more in the future," according to the Foundation's website.

This year's crop of 23 Fellows includes stone carver Nicholas Benson and quantum astrophysicist Nergis Mavalvala; Dabiri joins the ranks of Caltech's previous MacArthur Fellows, including 2008 awardee Alexei Kitaev.

Unlike most MacArthur recipients—who are awakened with an early morning phone call announcing their prize—Dabiri, who is an associate professor of aeronautics and bioengineering at Caltech, received an email.

"The Foundation had one of the digits incorrect in my cell phone number, so they called the wrong guy," Dabiri says. "The email asked me to call the Foundation immediately, but since I had always heard that the winners receive a phone call, I assumed they just wanted my help getting in touch with a colleague. That's when I heard the good news—and I was completely shocked! Between proposal deadlines, papers, and preparing lecture notes, this wasn't at all on my radar."

Dabiri is the head of Caltech's Biological Propulsion Laboratory, where he and his colleagues examine the mechanics and dynamics of biological propulsion, which has applications for the design of new types of biologically inspired propulsion systems. Although Dabiri is notably a nonswimmer, and admits to sinking "like a stone" in the water, much of his work is focused on jellyfish, which he studies in a 40-meter-long, 8,000-gallon water tunnel at Caltech. Jellyfish can slice through the water with extreme efficiency and may generate high-powered jets when under attack. One outcome of this work has been the design of propellers that create vortex rings like those of jellyfish. In other research, Dabiri and his colleagues have developed a model that explains how some of the ocean's tiniest swimming animals may have a huge impact on large-scale ocean mixing.

Dabiri also is interested in developing new and better ways of harnessing wave and wind energy as power sources. "I became inspired by observations of schooling fish, and the suggestion that there is constructive hydrodynamic interference between the wakes of neighboring fish," he says. During these observations, Dabiri noticed that some of the vortices left behind by fish swimming in a school rotate clockwise, while others rotate counter-clockwise. He realized this could have relevance to wind farms, which are commonly hampered by a lack of space.

The large-propeller horizontal-axis wind turbines most commonly seen on wind farms require a substantial amount of land to perform properly; in contrast, vertical turbines, which use a vertical rotor, can be placed on smaller plots of land in a denser pattern. Dabiri and his colleagues determined that placing vertical-axis turbines in arrays with certain strategic configurations might allow the turbines to work more efficiently as a result of their relationship to others around them—just as in schools of fish.

Such configurations of vertical turbines are currently being put to the test on an experimental wind farm under construction in the high desert north of Los Angeles.

Dabiri, who holds a bachelor's degree from Princeton University, obtained a Master of Science degree in aeronautics from Caltech in 2003 and, in April 2005, a PhD in bioengineering with a minor in aeronautics from Caltech. In May 2005, he joined the Caltech faculty as an assistant professor; he was promoted to associate professor in 2009. In 2008, Dabiri was the recipient of an Office of Naval Research Young Investigator award for research in bioinspired propulsion, and was named one of Popular Science magazine's "Brilliant 10" young scientists to watch; in 2009, he was given a Presidential Early Career Award for Scientists and Engineers.

"We are proud and delighted that John has received this acknowledgment of his innovative approach to research and his engineering education and training at Caltech," says Ares J. Rosakis, the Theodore von Kármán Professor of Aeronautics, professor of mechanical engineering, and chair of the Division of Engineering and Applied Science.

"I'm extremely grateful for the MacArthur award, but it is the result of the efforts of many people," Dabiri says. "I've been blessed with generous mentors at every stage of life: from my parents, to my professors at Princeton, to Mory Gharib here at Caltech. It's also a credit to the students and postdocs in my lab, who work very hard on challenging and often risky research topics, and to my collaborators—especially biologists like Jack Costello at Providence College and Sean Colin at Roger Williams University—who gave me a deeper appreciation for the beautiful subtleties of jellyfish. I hope they all know how grateful I am."

"John has this extraordinary talent for making complex science and engineering issues simple through his deep understanding of these subjects," says Gharib, the Hans W. Liepmann Professor of Aeronautics, professor of bioinspired engineering, and Caltech's vice provost. "Getting ideas from jellyfish to design better propulsion systems requires an exceptionally creative mind. Receiving the MacArthur Fellowship award for his work on aquatic propulsion is a fantastic achievement for a nonswimmer."

"As for how I'll spend the money, I'm going to have to pray about that," Dabiri says. "This is an opportunity I never imagined I would have, and I want to make the most of it."

He does, however, have one idea: "I think I'll start with swimming lessons, so that I can finally get up close and personal with the jellyfish I've been studying from afar."

For more information on the 2010 MacArthur Fellows, visit the Foundation website at

Kathy Svitil
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Caltech Receives $10 Million in Gifts to Help Launch New Terrestrial Hazard Center

Center will focus on developing innovative ways to reduce the risks and costs of natural hazards

PASADENA, Calif.-In an effort to find ways to minimize the damage caused by natural hazards, the California Institute of Technology (Caltech) has established the Terrestrial Hazard Observation and Reporting Center (THOR), funded by $6.7 million from Foster and Coco Stanback of Irvine, California, and $3.35 million from the Gordon and Betty Moore matching program.

THOR will have the unique mandate of bringing together-under one program-innovative efforts to reduce the risks and costs associated with natural hazards. The center will span two divisions at Caltech, Geological and Planetary Sciences (GPS) and Engineering and Applied Science (EAS).

The study of natural hazards and solutions is ordinarily undertaken in separate academic disciplines with little intellectual interaction. THOR will provide a new focal point that will unify these efforts and allow investigators to focus on critical societal issues.

"From the current flooding in Pakistan, to the recent earthquake in Haiti, to the constant threat of wildfires in our own backyard, we are consistently reminded of the devastating impact natural hazards can have on society," says Caltech president Jean-Lou Chameau. "Now, with the generous support of Foster and Coco Stanback, Caltech scientists and engineers will be able to study these critical issues in a unique interdisciplinary environment.  THOR will help communities around the world determine how to best prepare for, anticipate, and respond to various natural hazards, hopefully saving lives in the process." 

Natural hazards that will fall under THOR's purview include global climate change, earthquakes, tsunamis, landslides, wildfires, and extreme weather events such as droughts, among others.

By providing support for the development of techniques and physical inventions, THOR will focus on practical societal aspects of natural hazards and their public policy implications.

For instance, THOR may help guide the distribution of limited resources following a major hazard such as an earthquake or tsunami, or lead to early-warning systems.

"The interdisciplinary and interactive nature of engineering at Caltech allows us to translate scientific knowledge and discovery into applications with direct societal impact," says Ares Rosakis, the von Kármán Professor of Aeronautics, professor of mechanical engineering, and chair of the division of Engineering and Applied Science. "One of the areas of pioneering research and innovation made possible by THOR is seismo-engineering. The boundaries of seismo-engineering are fuzzy ones and lie exactly in the interface between seismology and earthquake engineering.  We are delighted to have the opportunity to explore these boundaries."

Caltech has a number of highly visible areas of expertise that already touch on natural-hazard issues, including the Seismological Laboratory, the Linde Center for Global Environmental Science, missions of the Caltech-managed Jet Propulsion Laboratory (JPL) that provide critical high-precision data on Earth's climate and environment, multiple studies supported by the Keck Institute for Space Studies (KISS) focused on future Earth-observing missions, and the Resnick Institute for Science, Energy, and Sustainability.   

"The THOR center will provide a unique platform for collaboration among scientists, students, and policymakers, empowering them with the extensive resources of Caltech and the Jet Propulsion Laboratory," says THOR donor Foster Stanback. "By linking our eyes in the sky with the many eyes on the ground, we will be far better prepared to anticipate, mitigate, and eliminate many environmental hazards."

THOR's attention and resources will be applied in several ways, including the dissemination of the results of work supported by THOR; supporting efforts to transfer ideas and technologies that show promise of practical implementation; and prioritizing, seeding, and nurturing ideas encompassing research activities, along with the invention of technologies.

"THOR will give faculty in GPS and EAS the opportunity to develop innovative new ways to help mitigate the consequences and costs of the natural hazards society faces, from climate change to earthquakes to water scarcity," says Ken Farley, the W.M. Keck Foundation Professor of Geochemistry and chair of the division of Geological and Planetary Sciences. "This very applied research is difficult to support from federal sources, so my hope is that the gift will catalyze entirely new endeavors. THOR will also allow us to bring to our educational program a new focus on the societal and policy implications and relevance of our work."

The center will be housed within the newly renovated Linde + Robinson Laboratory on the Caltech campus.

Jon Weiner
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Two Caltech Scientists Receive 2010 NIH Director's Pioneer Awards

Michael Roukes, Pamela Bjorkman recognized for their "highly innovative approaches" to biomedical research

PASADENA, Calif.—Two scientists from the California Institute of Technology (Caltech) have been recognized by the National Institutes of Health (NIH) for their innovative and high-impact biomedical research programs.

Michael Roukes, professor of physics, applied physics, and bioengineering, and co-director of the Kavli Nanoscience Institute, and

Pamela Bjorkman, Caltech's Max Delbrück Professor of Biology and a Howard Hughes Medical Institute investigator, now join the 81 Pioneers—including Caltech researchers Rob Phillips and Bruce Hay—who have been selected since the program's inception in 2004.

"NIH is pleased to be supporting scientists from across the country who are taking considered risks in a wide range of areas in order to accelerate research," said NIH Director Francis S. Collins in announcing the awards. "We look forward to the result of their work."

According to its website, the program provides each investigator chosen with up to $500,000 in direct costs each year for five years to pursue what the NIH refers to as "high-risk research," and was created to "support individual scientists of exceptional creativity who propose pioneering—and possibly transforming—approaches to major challenges in biomedical and behavioral research."

For Roukes, that means using "nanoscale tools to push biomedical frontiers." Specifically, he plans to leverage advances in nanosystems technology, "an approach that coordinates vast numbers of individual nanodevices into a coherent whole," he explains.

The goal? To create tiny "chips" that can be used to rapidly identify which specific bacteria are plaguing an individual patient—quickly, at the patient's bedside, and without the need for culturing. Similar chips, he says, will be capable of "obtaining physiological 'fingerprints' from exhaled breath" for use in disease diagnostics.

Roukes says the chips will also provide new approaches to cancer research through the analysis of cell mechanics and motility, and will provide less-costly ways to screen libraries of therapeutic drug candidates. Roukes's highly collaborative efforts are aimed at jump-starting what he calls a "nanobiotech incubator" at Caltech.

Roukes received his PhD in physics in 1985 from Cornell University. He has been at Caltech since 1992, and was named founding director of the Kavli Nanoscience Institute in 2004.

Bjorkman's Pioneer project will focus on ways to improve the human immune response to HIV. "HIV/AIDS remains one of the most important current threats to global public health," she says. "Although humans can mount effective immune responses using antibodies against many other viruses, the antibody response to HIV in infected individuals is generally ineffective."

This, she believes, is the result of the "unusually low number and low density of spikes" on the surface membrane of the virus. Antibodies have two identical "arms" with which to attach to a virus or bacterium. In most cases, the density of spikes on a pathogen's surface is high enough that these arms can simultaneously attach to neighboring spikes. Not so with HIV; because its spikes are so few and far between, antibodies tend to bind with only one arm attaching to a single spike. Such binding is weak, says Bjorkman, "much like if you were hanging from a bar with only one arm," and is easily eliminated by viral mutations.

That is why Bjorkman is proposing "a new methodology, designed to screen for and produce novel anti-HIV binding proteins that can bind simultaneously to all three monomers in an HIV spike trimer." A trimer is a protein made of three identical macromolecules; if an antibody can bind to all three proteins at one time, it will "interact very tightly and render the low spike density of HIV and its high mutation rate irrelevant to effective neutralization," Bjorkman explains.

Bjorkman received her PhD in biochemistry and molecular biology in 1984 from Harvard University. She has been at Caltech since 1989, and was named the Delbrück Professor in 2004.

Lori Oliwenstein
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Schooling Fish Offer New Ideas for Wind Farming

The quest to derive energy from wind may soon be getting some help from California Institute of Technology (Caltech) fluid-dynamics expert John Dabiri-and a school of fish.

As head of Caltech's Biological Propulsion Laboratory, Dabiri studies water- and wind-energy concepts that share the theme of bioinspiration: that is, identifying energy-related processes in biological systems that may provide insight into new approaches to-in this case-wind energy.

"I became inspired by observations of schooling fish, and the suggestion that there is constructive hydrodynamic interference between the wakes of neighboring fish," says Dabiri, associate professor of aeronautics and bioengineering at Caltech. "It turns out that many of the same physical principles can be applied to the interaction of vertical-axis wind turbines."

The biggest challenge with current wind farms is lack of space. The horizontal-axis wind turbines most commonly seen-those with large propellers-require a substantial amount of land to perform properly. "Propeller-style wind turbines suffer in performance as they come in proximity to one another," says Dabiri.

In the Los Angeles basin, the challenge of finding suitable space for such large wind farms has prevented further progress in the use of wind energy. But with help from the principles supplied by schooling fish, and the use of vertical-axis turbines, that may change.

Vertical turbines-which are relatively new additions to the wind-energy landscape-have no propellers; instead, they use a vertical rotor. Because of this, the devices can be placed on smaller plots of land in a denser pattern. Caltech graduate students Robert Whittlesey and Sebastian Liska researched the use of vertical-axis turbines on small plots during a class research project supervised by Dabiri. Their results suggest that there may be substantial benefits to placing vertical-axis turbines in a strategic array, and that some configurations may allow the turbines to work more efficiently as a result of their relationship to others around them-a concept first triggered by examining schools of fish.

In current wind farms, all of the turbines rotate in the same direction. But while studying the vortices left behind by fish swimming in a school, Dabiri noticed that some vortices rotated clockwise, while others rotated counter-clockwise. Dabiri therefore wants to examine whether alternating the rotation of vertical-axis turbines in close proximity will help improve efficiency. The second observation he made studying fish-and seen in Whittlesey and Liska's simulation-was that the vortices formed a "staircase" pattern, which contrasts with current wind farms that place turbines neatly in rows.

Whittlesey and Liska's computer models predicted that the wind energy extracted from a parcel of land using this staggered placement approach would be several times that of conventional wind farms using horizontal-axis turbines. Once they've identified the optimal placement, Dabiri believes it may be possible to produce more than 10 times the amount of energy currently provided by a farm of horizontal turbines. The results are sufficiently compelling that the Caltech group is pursuing a field demonstration of the idea.

Dabiri has purchased two acres of land north of Los Angeles, where he is establishing the Caltech Field Laboratory for Optimized Wind Energy (FLOWE). The pilot program at the site will feature six vertical turbines on mobile platforms.

Dabiri and his team will systematically move the turbines around, testing various configurations to find the most efficient patterns.

"Our goal is to demonstrate a new technology that enables us to extract significantly more wind energy from a given parcel of land than is currently possible using existing methods," says Dabiri. "We want to take advantage of constructive aerodynamic interference between closely spaced vertical-axis wind turbines. Our results can potentially make better use of existing wind farms, allow for wind farms to be located closer to urban centers-reducing power transmission costs-and reduce the size of offshore installations."

Three of Dabiri's turbines are being provided in partnership with Windspire Energy. In exchange for the use of the turbines, Dabiri will share his research results with the company. Each Windspire turbine stands approximately 30 feet tall and 4 feet wide, and can generate up to 1.2 kW of power.

"This leading-edge project is a great example of how thinking differently can drive meaningful innovation," says Windspire Energy President and CEO Walt Borland. "We are very excited to be able to work with Dr. Dabiri and Caltech to better leverage the unique attributes of vertical-axis technology in harvesting wind energy."   

Three turbines from another manufacturer have been purchased; the six turbines give the pilot facility a total power capacity of 15 kW, enough to power several homes.

"This project is unique in that we are conducting these experiments in real-world conditions, as opposed to on the computer or in a laboratory wind tunnel," says Dabiri. "We have intentionally focused on a field demonstration because this can more easily facilitate a future expansion of the project from basic science research into a power-generating facility. Our ability to make that transition will depend on the results of the pilot program."

The initial phase of the study will attempt to demonstrate which configuration of units will improve power output and performance relative to a horizontal-axis wind turbine farm with a similar sized plot of land.

"In the future, we hope to transition to power-generation experiments in which the generated power can be put to use either locally or via a grid connection," Dabiri says.

The American Recovery and Reinvestment Act provided partial funding for this project.

For more information on FLOWE, visit:

Jon Weiner

Spiders at the Nanoscale: Molecules that Behave Like Robots

PASADENA, Calif.—A team of scientists from Columbia University, Arizona State University, the University of Michigan, and the California Institute of Technology (Caltech) have programmed an autonomous molecular "robot" made out of DNA to start, move, turn, and stop while following a DNA track.

The development could ultimately lead to molecular systems that might one day be used for medical therapeutic devices and molecular-scale reconfigurable robots—robots made of many simple units that can reposition or even rebuild themselves to accomplish different tasks.

A paper describing the work appears in the current issue of the journal Nature.

The traditional view of a robot is that it is "a machine that senses its environment, makes a decision, and then does something—it acts," says Erik Winfree, associate professor of computer science, computation and neural systems, and bioengineering at Caltech.

Milan N. Stojanovic, a faculty member in the Division of Experimental Therapeutics at Columbia University, led the project and teamed up with Winfree and Hao Yan, professor of chemistry and biochemistry at Arizona State University and an expert in DNA nanotechnology, and with Nils G. Walter, professor of chemistry and director of the Single Molecule Analysis in Real-Time (SMART) Center at the University of Michigan in Ann Arbor, for what became a modern-day self-assembly of like-minded scientists with the complementary areas of expertise needed to tackle a tough problem.

Shrinking robots down to the molecular scale would provide, for molecular processes, the same kinds of benefits that classical robotics and automation provide at the macroscopic scale. Molecular robots, in theory, could be programmed to sense their environment (say, the presence of disease markers on a cell), make a decision (that the cell is cancerous and needs to be neutralized), and act on that decision (deliver a cargo of cancer-killing drugs).

Or, like the robots in a modern-day factory, they could be programmed to assemble complex molecular products.  The power of robotics lies in the fact that once programmed, the robots can carry out their tasks autonomously, without further human intervention.

With that promise, however, comes a practical problem: how do you program a molecule to perform complex behaviors?

"In normal robotics, the robot itself contains the knowledge about the commands, but with individual molecules, you can't store that amount of information, so the idea instead is to store information on the commands on the outside," says Walter. And you do that, says Stojanovic, "by imbuing the molecule's environment with informational cues."

"We were able to create such a programmed or 'prescribed' environment using DNA origami," explains Yan. DNA origami, an invention by Caltech Senior Research Associate Paul W. K. Rothemund, is a type of self-assembled structure made from DNA that can be programmed to form nearly limitless shapes and patterns (such as smiley faces or maps of the Western Hemisphere or even electrical diagrams). Exploiting the sequence-recognition properties of DNA base pairing, DNA origami are created from a long single strand of DNA and a mixture of different short synthetic DNA strands that bind to and "staple" the long DNA into the desired shape. The origami used in the Nature study was a rectangle that was 2 nanometers (nm) thick and roughly 100 nm on each side.

The researchers constructed a trail of molecular "bread crumbs" on the DNA origami track by stringing additional single-stranded DNA molecules, or oligonucleotides, off the ends of the staples. These represent the cues that tell the molecular robots what to do—start, walk, turn left, turn right, or stop, for example—akin to the commands given to traditional robots. 

The molecular robot the researchers chose to use—dubbed a "spider"—was invented by Stojanovic several years ago, at which time it was shown to be capable of extended, but undirected, random walks on two-dimensional surfaces, eating through a field of bread crumbs.

To build the 4-nm-diameter molecular robot, the researchers started with a common protein called streptavidin, which has four symmetrically placed binding pockets for a chemical moiety called biotin. Each robot leg is a short biotin-labeled strand of DNA, "so this way we can bind up to four legs to the body of our robot," Walter says. "It's a four-legged spider," quips Stojanovic. Three of the legs are made of enzymatic DNA, which is DNA that binds to and cuts a particular sequence of DNA. The spider also is outfitted with a "start strand"—the fourth leg—that tethers the spider to the start site (one particular oligonucleotide on the DNA origami track). "After the robot is released from its start site by a trigger strand, it follows the track by binding to and then cutting the DNA strands extending off of the staple strands on the molecular track," Stojanovic explains.

"Once it cleaves," adds Yan, "the product will dissociate, and the leg will start searching for the next substrate." In this way, the spider is guided down the path laid out by the researchers. Finally, explains Yan, "the robot stops when it encounters a patch of DNA that it can bind to but that it cannot cut," which acts as a sort of flypaper.

Although other DNA walkers have been developed before, they've never ventured farther than about three steps. "This one," says Yan, "can walk up to about 100 nanometers. That's roughly 50 steps."

"This in itself wasn't a surprise," adds Winfree, "since Milan's original work suggested that spiders can take hundreds if not thousands of processive steps. What's exciting here is that not only can we directly confirm the spiders' multistep movement, but we can direct the spiders to follow a specific path, and they do it all by themselves—autonomously."

In fact, using atomic force microscopy and single-molecule fluorescence microscopy, the researchers were able to watch directly spiders crawling over the origami, showing that they were able to guide their molecular robots to follow four different paths.

"Monitoring this at a single molecule level is very challenging," says Walter. "This is why we have an interdisciplinary, multi-institute operation. We have people constructing the spider, characterizing the basic spider. We have the capability to assemble the track, and analyze the system with single-molecule imaging. That's the technical challenge." The scientific challenges for the future, Yan says, "are how to make the spider walk faster and how to make it more programmable, so it can follow many commands on the track and make more decisions, implementing logical behavior."

"In the current system," says Stojanovic, "interactions are restricted to the walker and the environment. Our next step is to add a second walker, so the walkers can communicate with each other directly and via the environment. The spiders will work together to accomplish a goal." Adds Winfree, "The key is how to learn to program higher-level behaviors through lower-level interactions." 

Such collaboration ultimately could be the basis for developing molecular-scale reconfigurable robots—complicated machines that are made of many simple units that can reorganize themselves into any shape—to accomplish different tasks, or fix themselves if they break.  For example, it may be possible to use the robots for medical applications. "The idea is to have molecular robots build a structure or repair damaged tissues," says Stojanovic.

"You could imagine the spider carrying a drug and bonding to a two-dimensional surface like a cell membrane, finding the receptors and, depending on the local environment," adds Yan, "triggering the activation of this drug."

Such applications, while intriguing, are decades or more away. "This may be 100 years in the future," Stojanovic says. "We're so far from that right now." 

"But," Walter adds, "just as researchers self-assemble today to solve a tough problem, molecular nanorobots may do so in the future."

The other coauthors on the paper, "Molecular robots guided by prescriptive landscapes," are Kyle Lund and Jeanette Nangreave from Arizona State University; Anthony J. Manzo, Alexander Johnson-Buck, and Nicole Michelotti from the University of Michigan; Nadine Dabby from Caltech; and Steven Taylor and Renjun Pei from Columbia University. The work was supported by the National Science Foundation, the Army Research Office, the Office of Naval Research, the National Institutes of Health, the Department of Energy, the Searle Foundation, the Lymphoma and Leukemia Society, the Juvenile Diabetes Research Foundation, and a Sloan Research Fellowship.

Kathy Svitil

Caltech Biologists Link Gut Microbial Equilibrium to Inflammatory Bowel Disease

PASADENA, Calif.—We are not alone—even in our own bodies. The human gut is home to 100 trillion bacteria, which, for millions of years, have co-evolved along with our digestive and immune systems. Most people view bacteria as harmful pathogens that cause infections and disease. Other, more agreeable, microbes (known as symbionts) have taken a different evolutionary path, and have established beneficial relationships with their hosts. Still other microbes may be perched somewhere in between, according to research by biologists at the California Institute of Technology (Caltech) that offers new insight into the causes of inflammatory bowel disease (IBD) and colon cancer.

A paper about their work appears in the April 22 issue of the journal Cell Host & Microbe


"It has been proposed that the coupled equilibrium between potentially harmful and potentially beneficial bacteria in the gut mediates health versus disease," says Sarkis K. Mazmanian, assistant professor of biology at Caltech. "If the balance is altered," say, by changes in diet, the effects of stress, or the use of antibiotics, "then the immune response in the intestines is also changed." This altered host–microbe relationship, called dysbiosis, has been linked to IBD and colon cancer as well as to obesity and diabetes.

Close to a thousand different species of bacteria reside in the gut, which makes understanding the consequences of dysbiosis a challenge. One way of studying the effects of a balanced host–microbe relationship, and how it arises in the first place, is to change experimentally the relative population size of the microbe. That's exactly what Mazmanian and graduate student Janet Chow accomplished in a bacterium called Helicobacter hepaticus.

Helicobacter hepaticus has an unusual modus operandi. It is not an opportunistic pathogen like the bacteria that cause diseases such as tuberculosis or strep throat, nor is it a beneficial symbiont. While H. hepaticus can persist for a lifetime in the gut of a healthy organism without causing any ill effects, it causes syndromes similar to IBD in immunocompromised mice—animals with artificially depressed or inactive immune systems. "Perhaps this organism is somewhere within the evolutionary spectrum between pathogen and symbiont," says Mazmanian. The authors have coined the term "pathobiont" to describe the unique lifestyle of H. hepaticus and the relationship it establishes with its host.

Mazmanian and Chow suspected that the effect of the bug's presence—whether it lives in quiet coexistence with its host or causes disease—may be determined by its ability to communicate with and, more importantly, to modify the immune system of its host.

To examine this possibility, Chow genetically altered the bacterium to inactivate its "secretion system." The secretion system is a collection of proteins the microbe uses to send chemical messages to its host; Mazmanian says it represents a biological "needle and syringe" that delivers bacterial molecules directly into eukaryotic cells. Although the specific functions and identities of these chemicals are unknown, they appear to establish a truce between the bug and the host's immune system.

When Chow genetically disrupted the secretion system—shutting off this communication—she saw two unexpected and intriguing effects. First, the size of the H. hepaticus population expanded dramatically, leading to dysbiosis. In turn, the host immune system ramped up its activity. This manifested in inflammation—the body's response to infection or injury.

"The bacteria appear to have struck a deal with their host," Mazmanian says. They keep their own numbers low so they don't overwhelm the immune system, and in return, the immune system leaves them alone. "The bacteria need the secretion system to put the host in 'don't attack' mode." In return, the presence of the bacteria does not induce inflammation, as would be the case with a pathogen that has not evolved a similar "agreement."

"There has to be communication. It could be peaceful—as is the case for symbionts—or it could be an argument—as is the case for pathogens. But when this molecular dialogue breaks down, it's probably harmful to both microbe and man," Mazmanian says.

Disrupt that communication, and the balance gets thrown out of whack. "Inflammation leads to cancer, and this bacterium has been associated with inflammation and colon cancer in animals," he says. Understanding if dysbiosis causes disease in humans could lead to therapies based on restoring the healthy microbial balance in the gut.

The work in the paper, "A Pathobiont of the Microbiota Balances Host Colonization and Intestinal Inflammation," was supported by funding from the Emerald Foundation and the Crohn's & Colitis Foundation of America. The inception of the project was supported by a Damon Runyon-Rachleff Innovation Award from the Damon Runyon Cancer Research Foundation.


Kathy Svitil

R. David Middlebrook, 80

Pasadena, Calif.-R. David Middlebrook, emeritus professor of electrical engineering at the California Institute of Technology (Caltech), passed away on April 16. He was 80 years old.

Middlebrook died at his home with family by his side. Born in 1929, he was raised in Newcastle, England, and came to the United States in 1952 on the Queen Mary.

Middlebrook wrote a pioneering transistor textbook that included mathematical models to help engineers use transistors in their circuit designs; a later book focused on differential amplifiers. In 1970, he founded the Caltech Power Electronics Group. The group graduated 36 PhD students, many of whom are now leaders in the power electronics field.

A distinguished international lecturer, Middlebrook was particularly noted for presenting complex material in a simple, interesting, effective, and entertaining manner. He was especially interested in design-oriented circuit analysis and measurement techniques, and his Structured Analog Design course was attended by design engineers and managers from the United States, Canada, and Europe. 

Middlebrook also taught inhouse analog-design courses for more than 20 years, working with companies such as AT&T, Boeing, Ericsson, Hewlett Packard, Hughes Aircraft, IBM, Motorola, Philips, Tektronix, TRW, and many others.

He is well known for his Extra Element Theorem, which gives simple formulas for the effects of adding a single element to a circuit. This theorem and its variations are widely used in circuit design and measurements.  

Middlebrook received his BA and MA degrees from the University of Cambridge, and his MS and PhD degrees from Stanford University. He joined Caltech as an assistant professor in 1955; he was named associate professor in 1958, and professor in 1965. He became emeritus in 1998.

In 1996, the Caltech student body recognized him as an outstanding educator with its Feynman Prize for Excellence in Teaching.

"For more than 40 years, Dr. Middlebrook taught his students a way of thinking, not just a body of knowledge," the award's citation noted. "[H]e demonstrated to thousands of delighted students how to simplify complex subjects and how to marry theory and experiment. He also taught them a lesson in scientific modesty, as he constantly adopted the best solutions generated by his students."

Middlebrook was a Life Fellow of the IEEE and a Fellow of the IEE (UK). In addition to the Feynman Prize, he was the recipient of the Franklin Institute's Edward Longstreth Medal, the IEEE's Millennium and Centennial medals and its William E. Newell Power Electronics Award, and the Award for Excellence in Teaching, presented by the Board of Directors of the Associated Students of the California Institute of Technology.

He leaves behind a wife, Val, sons John Garrison and Joe Middler, daughter Trudy Wolsky, and grandchildren Chad and Teagan.

Jon Weiner
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Caltech-Led Team Designs Novel Negative-Index Metamaterial that Responds to Visible Light

Uniquely versatile material could be used for more efficient light collection in solar cells

PASADENA, Calif.—A group of scientists led by researchers from the California Institute of Technology (Caltech) has engineered a type of artificial optical material—a metamaterial—with a particular three-dimensional structure such that light exhibits a negative index of refraction upon entering the material. In other words, this material bends light in the "wrong" direction from what normally would be expected, irrespective of the angle of the approaching light.

This new type of negative-index metamaterial (NIM), described in an advance online publication in the journal Nature Materials, is simpler than previous NIMs—requiring only a single functional layer—and yet more versatile, in that it can handle light with any polarization over a broad range of incident angles. And it can do all of this in the blue part of the visible spectrum, making it "the first negative index metamaterial to operate at visible frequencies," says graduate student Stanley Burgos, a researcher at the Light-Material Interactions in Energy Conversion Energy Frontier Research Center at Caltech and the paper's first author.

"By engineering a metamaterial with such properties, we are opening the door to such unusual—but potentially useful—phenomena as superlensing (high-resolution imaging past the diffraction limit), invisibility cloaking, and the synthesis of materials index-matched to air, for potential enhancement of light collection in solar cells," says Harry Atwater, Howard Hughes Professor and professor of applied physics and materials science, director of Caltech's Resnick Institute, founding member of the Kavli Nanoscience Institute, and leader of the research team

What makes this NIM unique, says Burgos, is its engineering.

"The source of the negative-index response is fundamentally different from that of previous NIM designs," he explains. Those previous efforts used multiple layers of "resonant elements" to refract the light in this unusual way, while this version is composed of a single layer of silver permeated with "coupled plasmonic waveguide elements."

Surface plasmons are light waves coupled to waves of electrons at the interface between a metal and a dielectric (a non-conducting material like air). Plasmonic waveguide elements route these coupled waves through the material. Not only is this material more feasible to fabricate than those previously used, Burgos says, it also allows for simple "tuning" of the negative-index response; by changing the materials used, or the geometry of the waveguide, the NIM can be tuned to respond to a different wavelength of light coming from nearly any angle with any polarization. "By carefully engineering the coupling between such waveguide elements, it was possible to develop a material with a nearly isotopic refractive index tuned to operate at visible frequencies."

This sort of functional flexibility is critical if the material is to be used in a wide variety of ways, says Atwater. "For practical applications, it is very important for a material's response to be insensitive to both incidence angle and polarization," he says. "Take eyeglasses, for example. In order for them to properly focus light reflected off an object on the back of your eye, they must be able to accept and focus light coming from a broad range of angles, independent of polarization. Said another way, their response must be nearly isotropic. Our metamaterial has the same capabilities in terms of its response to incident light."

This means the new metamaterial is particularly well suited to use in solar cells, Atwater adds. "The fact that our NIM design is tunable means we could potentially tune its index response to better match the solar spectrum, allowing for the development of broadband wide-angle metamaterials that could enhance light collection in solar cells," he explains. "And the fact that the metamaterial has a wide-angle response is important because it means that it can 'accept' light from a broad range of angles. In the case of solar cells, this means more light collection and less reflected or 'wasted' light."

"This work stands out because, through careful engineering, greater simplicity has been achieved," says Ares Rosakis, chair of the Division of Engineering and Applied Science at Caltech and Theodore von Kármán Professor of Aeronautics and Mechanical Engineering.

In addition to Burgos and Atwater, the other authors on the Nature Materials paper, "A single-layer wide-angle negative index metamaterial at visible frequencies," are Rene de Waele and Albert Polman from the Foundation for Fundamental Research on Matter Institute for Atomic and Molecular Physics in Amsterdam. Their work was supported by the Energy Frontier Research Centers program of the Office of Science of the Department of Energy, the National Science Foundation, the Nederlandse Organisatie voor Wetenschappelijk Onderzoek, and "NanoNed," a nanotechnology program funded by the Dutch Ministry of Economic Affairs.

Lori Oliwenstein


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