New Technique Makes Tissues Transparent

PASADENA, Calif.-- If humans had see-through skin like a jellyfish, spotting disease like cancer would be a snap: Just look, and see a tumor form or grow.

But humans, of course, are not remotely diaphanous. "The reason a person is not transparent is that their tissues are highly scattering," sending light waves careening through the tissue instead of straight through, as they would through the tissue of that jellyfish, explains Changhuei Yang of the California Institute of Technology.

This scattering, in addition to rendering all of us opaque, makes the detection of disease a much trickier issue, requiring a host of diagnostic tests and procedures. But not, perhaps, for much longer, thanks to a new optical trick developed by Yang, an assistant professor of electrical engineering and bioengineering, and his colleagues, that counteracts the scattering of light and removes the distortion it creates in images.

A study describing the process appears in the February issue of the journal Nature Photonics.

It is well known that light scattering in a material is not exactly the random and unpredictable process one might imagine. In fact, scattering is deterministic, which means that the path that a beam of light takes as it traverses a particular slice of tissue and bounces and rebounds off of individual cells, is entirely predictable; if you again bounce light through that same swath of cells, it will scatter in exactly the same way.

The process is even reversible; if the individual photons of light that scattered through the tissue could be collected and sent back through the tissue, they'd bounce back along the same path and converge at the original spot from which they were sent. "The process is similar to the scattering of billiard balls on a pool table. If you can precisely reverse the paths and velocities of the billiard balls, you can cause the billiard balls to reassemble themselves into a rack," Yang explains.

Yang, along with his colleagues at Caltech, École Polytechnique Fédérale de Lausanne in Switzerland, and MIT, exploited this phenomenon to offset the murky nature of our tissues.

Their technique, called turbidity suppression by optical phase conjugation (TSOPC), is surprisingly simple. The scientists used a holographic crystal to record the scattered light pattern emerging from a 0.46-mm-thick piece of chicken breast. They then holographically played the pattern back through the tissue section to recover the original light beam. "This is similar to grabbing hold of the direction of time flow and turning it around; the time-reversed photons must retrace their trajectories through the tissue," Yang says. "The task is formidable though, as this is comparable to starting with a rack of 10 to the 18th power billiard balls (or photons), scattering them around the table, and attempting to reassemble them into a rack."

"Until we did this study, it wasn't clear that the effect will be observable with biological tissues. We were pleasantly surprised that the effect was readily observable and remarkably robust," Yang says. "This study opens up numerous possibilities in the use of optical time reversal in biomedicine."

One possible use of the technique is in photodynamic therapy, in which a highly focused beam of light is aimed at cancerous cells that have absorbed cell-killing light-sensitive compounds. When the light hits the cells, the compounds are activated and destroy the cells. Photodynamic therapy is most effective in treating cancers on the skin surface. Yang's technique, however, offers a way to concentrate light onto cancer-killing compounds located more deeply within tissue.

Yang's idea is to inject strongly light-scattering particles that are coated with light-activated cancer-killing drugs into diseased tissue. Shine a beam of light into the tissue, and it would be reflected off the scattering compounds as it bounces through the tissue. Some of the scattered light would return to the source, where it could be recorded as a hologram.

This hologram would contain information about the path that the scattered light took through the tissue, and, in effect, describe the optimal path BACK toward the light-scattering molecule--and the cancer-killing compounds. Playing back the signal with a stronger burst of light will then activate the therapeutic drugs, which kill the cancer cells.

In addition, the technique could offer a way to power miniature implants buried deep within tissues. "If you take a quick survey of what is out there at present, you will see that implants are fairly large," Yang says. "For example, a pacemaker is about the size of a cell phone. Why are they so big? A large part of the reason is because they need to carry their own power sources."

The key to making smaller implants, then--say, the size of a pen tip--is to eliminate the power sources. "I think implants that carry photovoltaic receivers are particularly promising," he says. "The effect can be applied to tailor light-delivery mechanisms to efficiently channel light into tissues and onto these implants."

Zahid Yaqoob, a postdoctoral fellow in electrical engineering at Caltech, performed most of the experiments reported in the paper. The other authors of the paper are Demetri Psaltis, professor of optics and dean of engineering, École Polytechnique Fédérale de Lausanne in Switzerland, and Michael S. Feld, a professor of physics at MIT. 

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Kathy Svitil
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Programming Biomolecular Self-Assembly Pathways

PASADENA, Calif.--Nature knows how to make proteins and nucleic acids (DNA and RNA) dance to assemble and sustain life. Inspired by this proof of principle, researchers at the California Institute of Technology have demonstrated that it is possible to program the pathways by which DNA strands self-assemble and disassemble, and hence to control the dynamic function of the molecules as they traverse these pathways.

The team invented a versatile DNA motif with three modular domains that can be made to interact with complementary domains in other species of the same motif. Rewiring these relationships changes the dynamic function of the system. To make it easier to design such systems, the researchers developed a graphical abstraction of the motif that can be used to write "molecular programs." As described in the January 17 issue of the journal Nature, the team experimentally demonstrated the execution of four such programs, each illustrating a different class of dynamic function.

The study was performed by a team of four at Caltech: Niles Pierce, associate professor of applied and computational mathematics and bioengineering; Peng Yin, senior postdoctoral scholar in bioengineering and computer science; Harry Choi, graduate student in bioengineering; and Colby Calvert, research technician.

Programming pathways is a bit like planning a road trip. The final destination might be important, but the true enjoyment is picking and traveling the route. In the test tube, the goal is not solely to direct the molecules to assemble into a target structure, but to engage them in a sequence of maneuvers so as to implement a prescribed dynamic function before the system reaches equilibrium. The energy to power the reactions is stored in the molecules themselves. Each molecule is initially trapped in a high-energy state so that it can release this energy as it engages in handshakes with other molecules.

A molecular program is written and executed in four steps. First, the intended assembly and disassembly pathways are described using a graphical abstraction called a "reaction graph." This molecular program is then translated into molecular mechanisms described at the level of base pairing between individual complementary bases. Computational design algorithms developed in the group are then used to encode this mechanism into the DNA sequences. Finally, the program is executed by mixing the physical molecules.

To demonstrate this approach, the team experimentally demonstrated a variety of dynamic functions: catalytic formation of branched junctions, cross-catalytic circuitry with exponential system kinetics, triggered dendritic growth of molecular "trees," and autonomous locomotion of a molecular bipedal walker.

As Pierce describes it, these results take them closer to achieving a long-term goal of creating a "compiler for biomolecular function"--an automated design tool that takes as input a molecular program and provides as output a set of biomolecules that execute the desired function. He remarks, "It's about time for the stone age of molecular compilers to begin." 

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Elisabeth Nadin
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Ortiz Wins Inaugural Prize in Solid Mechanics

PASADENA, Calif.--Michael Ortiz, the Hayman Professor of Aeronautics and Mechanical Engineering at the California Institute of Technology, is the first winner of the Rodney Hill Prize in Solid Mechanics. The newly established international prize, which will be awarded every four years, is also the first of its kind in this field.

The Hill Prize, sponsored by scientific publisher Elsevier Limited and awarded under the auspices of the International Union of Theoretical and Applied Mechanics, will be bestowed in August 2008 at the Union's 22nd Congress in Adelaide, Australia. Ortiz will receive a plaque and $25,000.

Ortiz is being recognized for several contributions within the past decade, among them a new method for computing plastic deformation. His Caltech colleague, mechanics and materials science professor Kaushik Bhattacharya, describes Ortiz's formulation as "a combination of the cutting edge of mechanics and the cutting edge of mathematics." Plastic deformation reshapes a material without breaking it, like stretching a piece of Silly Putty, in incremental steps. Ortiz developed the incremental variational principle, which allows the computation of plastic deformations as they proceed. "These processes immediately affect applications ranging from the most mundane engineering to the kind of sophisticated things that go into modern manufacturing," says Bhattacharya.

Another of Ortiz's contributions, which he calls the quasi-continuum method, was developed in collaboration with Rob Phillips, professor of applied physics and mechanical engineering at Caltech, while they were both at Brown University. The method forms a bridge between the way engineers describe mechanical properties of materials at the scale of the atom and the way they describe these properties at a larger scale.

Atomistic physics, at the scale of nanometers, applies quantum mechanics to the study of how energy interacts with matter. At the scale of micrometers, continuum mechanics treats an object's substance, or matter, as uniformly changing, and a different set of physical rules applies. The crux of the problem, says Bhattacharya, is that "the way we describe the physics at the atomistic scale is different from how we describe it at the continuum scale. But the properties you observe at the larger scale are the sum total of all the properties at every scale leading up to it. This formula unites the scales.

"The quasi-continuum method is the first rigorous way of approaching this problem," Bhattacharya notes. "Most approaches are ad hoc. This is a method that goes down to fundamental physics and mathematics to do it in a seamless manner. It has beautiful mathematics and physics in it and has a really fantastic computational structure. It was so far ahead of its time when they started doing this around 10 years ago. When you see it you say, 'That's exactly the way to do it!'"

Ortiz says he feels greatly honored to win the prize because of the recognition that it brings to theoretical and computational mechanics. "I have always enjoyed working closely with mathematicians, physicists, and chemists, and I hope that this prize will underscore the importance of those collaborations," he says. "I am greatly indebted to my brilliant students, who have been an inexhaustible source of energy and enthusiasm; to my colleagues and collaborators over the years, from whom I have learned most of what I know; and to my family for their constant and unconditional support."

According to Bhattacharya, the Hill Prize is intended to be the first highly and internationally visible prize for all of mechanics. Its analogue for fluid mechanics, the Batchelor Prize, was created at the same time and awarded to Caltech alumnus Howard Stone, the Joseph Professor of Engineering and Applied Mathematics at Harvard University.

About Ortiz's achievement Bhattacharya says, "I was not surprised that he won, because Michael is that caliber a person. He is extraordinarily creative. Every time you talk to him he has a new idea, and his ideas are really radical departures from what people have done in the field."

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Elisabeth Nadin
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Pulselike and Cracklike Ruptures in Earthquake Experiments

Lab experiments that mimic the way the ground moves during destructive earthquakes require some sophisticated equipment, and they yield valuable insights. Caltech scientists studying how sliding motion spreads along a fault interface conducted a series of experiments involving ultrafast digital cameras and high-speed laser velocimeters to replicate a range of realistic fault conditions.

The team documented for the first time a systematic variation in earthquake rupture patterns called pulselike and cracklike ruptures. The experiments also revealed that both types of ruptures can transition to a state known as supershear speed, which generates its own characteristic ground shaking. The results appeared in the November 27 issue of the journal Proceedings of the National Academy of Sciences.

The scientists include Xiao Lu, graduate student in aeronautics; Nadia Lapusta, assistant professor of mechanical engineering and geophysics; and Ares Rosakis, the von Kármán Professor of Aeronautics and Mechanical Engineering and director of the Graduate Aeronautical Laboratories.

Simple theoretical models of earthquake ruptures show they slide like a crack--the entire length of the fault slides for just about as long as the earthquake lasts. But slip models used by seismologists to match records of ground motions from past earthquakes have suggested a different mode of rupture, one that moves like a pulse. A pulse of slip would travel down the length of a fault like a ripple passing over the surface of a pond, with all motion contained in the ripple, and the fault surface "healing" in its wake.

The forces that build up on either side of a fault, known as tectonic loading, can vary greatly and lead to different types of fault slip behavior. "Numerical calculations of earthquake ruptures that use friction laws guided by laboratory experiments produce both crack- and pulselike modes, depending on how loaded the fault is," says Lapusta. "We set out to test the predictions of these calculations in our experimental study." Pulse modes are predicted by calculations where faults are less loaded, but to make a fault slip under these conditions, models have to assume that fault friction decreases as the fault slip gets faster. This behavior, called rate-weakening friction, has been of long-standing interest to Lapusta and to Thomas Heaton, professor of engineering seismology, whose influential work on slip pulses demonstrated their short duration, and who proposed rate-weakening friction as a likely explanation.

The experiments began with a 9.5-millimeter-thick photoelastic plate sliced at an angle through its length, simulating a fault in Earth's crust. Pressure on the two sides of the fault was applied incrementally at an angle to build up the different components of loading. To trigger an earthquake rupture, a nickel wire the diameter of a human hair was embedded in the plate interface and then electrically discharged, creating a small explosion followed by a spontaneously spreading rupture. Lasers measured the relative movements on each side of the fault after the shock, and a high-speed camera captured the movements in 5-microsecond intervals. The mini-explosions were repeated for various orientations of tectonic loading.

The experimental setup mimics conditions under which very large earthquakes rupture Earth's crust along major strike-slip faults like California's San Andreas fault or the Kunlun fault in northern Tibet. The initial experimental design was devised by Rosakis; Smits Professor of Geophysics, Emeritus Hiroo Kanamori; and their joint graduate student Kaiwen Xia, who is now a professor at the University of Toronto.

The new experimental results support the models that suggest faults can have pulselike ruptures. "This is the first time we observed this spontaneous pulselike rupture in an experiment that mimics crustal earthquakes. We proved its existence," says Lu.

The experiments also documented under what conditions pulselike ruptures arise. When the plate interface was oriented at a 70-degree angle to the direction of compression, the rupture propagated as a narrow pulse. At smaller angles, the pulses got wider, until they transitioned into cracklike sliding modes. These experimental observations demonstrate the role that tectonic loading plays in how earthquakes rupture, and imply that real faults are governed by rate-weakening friction.

Another experimental result is related to earthquake rupture speeds. Calculations since the 1970s have predicted phenomena known as supershear bursts, which would cause destructive, high-frequency ground motions. Rosakis, Kanamori, and Xia have demonstrated such bursts in their experiments in recent years. Supershear bursts were shown to have caused damage during the 1979 Imperial Valley, 1992 Landers, and 1999 Izmit, Turkey, earthquakes.

In the experiment by Lu, Lapusta, and Rosakis, supershear propagation is seen to arise during both pulselike and cracklike earthquake ruptures. "That's new--nobody has seen before that either of those modes could transition to supershear," says Rosakis. Shock waves generated by supershear propagation generate more ground shaking, he adds, and notes that with more details about exactly how earthquakes rupture, scientists can devise more sophisticated ways for buildings to survive the specific types of shaking that arise.

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Elisabeth Nadin
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Genetic Underpinnings of Wood Digestion by Termite Gut Microbes Revealed

PASADENA, Calif.--When termites are chewing on your home, your immediate thought probably isn't "I wonder how they digest that stuff?" But biologists have been gnawing on the question for more than a century. The key is not just the termite, but what lives in its gut. A multitude of genes from the microbes populating the hindgut of a termite have been sequenced and analyzed, and the findings reported today in the journal Nature.

California Institute of Technology associate professor of environmental microbiology Jared Leadbetter led a team of researchers from other universities, private industry, and the Department of Energy (DOE) in uncovering the genetic underpinnings and the roles of bacteria in wood digestion by "higher termites." These insects abound in tropical and subtropical ecosystems. What the team found, says Leadbetter, is "a comprehensive set of blueprints for the bacteria that help dismantle wood."

Prior to this study, only one gene--in the insect itself--had been connected to the termite's rare ability to digest and nourish itself with wood, a substance that is energy-rich but hard to break down. It had also long been suspected that the 250 bacterial species that crowd the pinhead volume of a higher termite's hindgut might be directly involved in the process. But there was no way of knowing their roles for sure, because most of the organisms die quickly when removed from their host. Although the first bacterium genome was sequenced in 1994, it was a few years before scientists even considered sequencing entire communities of multiple species of organisms.

Leadbetter and his colleagues proposed to the DOE Joint Genome Institute (JGI) that the gut community of the Costa Rican termite Nasutitermes be examined because it is abundant and it plays significant roles in the wood degradation that helps to renew ecosystems. Leadbetter joined forces with collaborators at JGI, Verenium Corporation's San Diego facilities, and INBio, the National Biodiversity Institute of Costa Rica. They sequenced and analyzed more than 80,000 genes encoded by many of the hindgut bacteria species. "This was a fairly risky project when we proposed it," says Leadbetter, because "in these abundant tropical termites, there was no compelling evidence that these microbes play direct roles in cellulose degradation."

When the results started coming in, "we all breathed a big sigh of relief, because it turned out to be a gold mine in there," Leadbetter says. They found nearly 1,000 genes that underlie roles in breaking down two of wood's main components, cellulose and xylan, into their component sugars. The degradation of cellulose and xylan requires an arsenal of enzymes because of the huge diversity of biochemical bonds in wood. "This isn't some soft paper or grass we're talking about," says Leadbetter. "It's a hard substrate." Wood is made of three tightly intertwined compounds; taking it apart is a challenge, and termites are among the few known animals that can do it.

Leadbetter and his colleagues hope to eventually uncover exactly how each gene is involved in degrading wood, and where the energy the termite derives from the wood goes. This has recently become a focus of interest for those interested in developing an effective, industrial method to convert wood into ethanol. The challenge lies in events at the start of the process, like those involved in breaking down cellulose and xylan. Leadbetter and his colleagues believe that by investigating the genes that underlie these primary reactions, better ways of manufacturing biofuel can eventually be developed.

The study also identified nearly 100 different species of bacteria called spirochetes that belong to the genus Treponema. This membership makes them closely related to the bacterium that causes syphilis and to other spirochetes implicated in Lyme disease and gum disease. In termites, though, the findings show that these spirochetes actually benefit the health of their hosts. The genome sequencing also showed that the spirochetes are active in processes that generate hydrogen, an energy-rich gas, from wood. Certain genes also indicate that gut spirochetes can essentially taste or smell hydrogen and will swim either to or from its sources in the gut. In general, Leadbetter says, it looks like "these bacteria differ from those that dominate the gut tracts of humans and other mammals in their broad capacity to swim in response to diverse chemical stimuli. This behavior may be relevant to effective wood degradation."

Other Caltech authors of the paper are Eric Matson, a postdoctoral scholar in environmental science and engineering; Xinning Zhang, a graduate student in environmental science and engineering; and Elizabeth Ottesen, a graduate student in biology. Group leaders are Dan Robertson of Verenium Corporation, Phil Hugenholtz of the JGI, Giselle Tamayo of INBio, and Eric Mathur, formerly of Diversa (now at Synthetic Genomics).

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Elisabeth Nadin
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Team to Compete in Project Enterprise Ideas Contest on PBS

PASADENA, Calif.--It all started last fall, in a classroom at Caltech. A team of students in Visiting Professor of Mechanical Engineering Ken Pickar's course, Product Design for the Developing World, decided to create wheelchairs for people in developing countries that could tackle the rugged terrain. With two bicycles and three creative brains contributing, the project took off.

"There is a lot of creativity in this class," says Pickar. "But, this particular group displayed an immense amount of ingenuity both on the engineering and business sides."

Rudy Roy, Ben Sexson and Dan Oliver, who have all since graduated, came up with the idea for the non-profit organization Intelligent Mobility International (IMI), which is now among four finalists for a contest on "NOW," a PBS series. The Project Enterprise Contest will showcase a team that is using business tools to tackle a social problem.

IMI is looking to help the 20 million people with disabilities in developing countries regain mobility. Currently, only 1 percent of those disabled people own their own wheelchairs, and those chairs tend to be ill-suited for the rough terrain that disabled people must cross in rural areas.

According to Roy, Guatemala was the best place to start their work.

"We had done some research there and built a small network. We could have tried out the project in Mexico, which is much closer, but we thought it would be best to try it first in a smaller country."

Guatemala, with a population of about 12 million, is the focus of Transitions, another nonprofit organization that works with the disabled community in that country. Transitions will help IMI determine who needs the wheelchairs most.

Sponsorships for the wheelchairs will sell for $300 in the U.S. Disabled Guatemalans will be able to contribute a small amount towards the chairs as well

Roy says the team is also trying to encourage other college students to get involved in global philanthropic causes.

"The world is becoming a smaller place with the social networking revolution, and we can now use Facebook and the Internet to connect people around the world to tackle these problems. If young people in our country knew what they could do to help, they would get involved in these issues-it's the only way we can create a more sustainable world."

Thomas Oliver, a junior at Caltech, says the project helped him realize that it is possible to start a business from scratch. He has found that working for IMI is completely different from the other jobs he has had on campus.

"It's a tiny, tiny business," says Oliver. "So, everything you do helps push it a little further."

NOW is offering to chronicle up-and-coming social entrepreneurs as they work to get a project off the ground. The four finalists were chosen by judges, but the winning team will be chosen by the public through a voting system that can be found online at http://www.pbs.org/now/enterprisingideas/poll.html. The polls close October 31, and a final team will be announced November 2.

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Jacqueline Scahill
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Alice on Trial, Redux

Pasadena, Calif.--When Alice revs her engine at the start of the Defense Advanced Research Projects Agency (DARPA) Urban Challenge qualifying rounds on October 27, multitudes of cameras will be pointing at her. But she'll only care about the eight cameras that will be facing away.

Alice is the tricked-out Ford E-350 van that has been revamped to autonomously navigate the vagaries of an urban setting. To do so, she sports eight cameras that feed information to computers at rates of hundreds of megabits per second. Six of those cameras face forward, one faces the rear, and one is mounted on a pan-tilt unit programmed to turn and look to the left and to the right.

Team Caltech leader Richard Murray, Everhart Professor of Control and Dynamical Systems, says there's good reason the team chose a setup in which several cameras and lasers feed visual information into decentralized computers. With multiple computers telling Alice about surrounding obstacles, "it's like having multiple parts of your brain telling you what to do," he says. The computers are arranged in a hierarchy, with "lower level" computers doing computations based on the information they receive and passing on results to higher levels, where the ultimate decision is made. This way, there's less chance of driving into an obstacle and more chance of staying on the path the cameras detect. Team Caltech also chose this setup because it could easily accommodate new sensors.

The Urban Challenge presents far greater complexities than the two previous Grand Challenges, which took place in the desert of Barstow, California. "In the desert challenge, you simply had to drive on flat spots," Murray says. The teams have road information from aerial photos and maps of this year's challenge site, a mock city at the George Air Force Base in Victorville, California. But, says Murray, "that's not the hard part. It's dealing with what's not on the map. We don't know where there will be obstacles or where other vehicles will be."

Team Caltech's attempts at winning the first two DARPA challenges were met with defeat. In 2004, Alice's predecessor Bob drove 1.3 miles before losing a fight with a barbed-wire fence. In communications theory, Alice and Bob stand for sender and receiver, so the next year, Bob gave way to Alice, who ended an eight-mile run at a concrete barrier. Now, Alice, redux, is one of 35 vehicles entering the qualifying round for this year's Urban Challenge. Murray is confident Team Caltech will advance to the final round, on November 3.

What makes the new challenge so difficult is not news to any driver--the rules come from the California driver's handbook. Any collision or damage wreaked gets the team automatically disqualified. Broken rules like turning without signaling or crossing a solid traffic line incur a time penalty. Each team will vie with up to 34 other vehicles that may qualify for the race, and DARPA may make things even trickier by including human-driven vehicles.

It would be impossible to imagine and prepare for every error that pops up, says Murray. Instead, he says, the team took the approach of following a sequence of actions to try to solve any dilemma. For example, if there were dirt on one sensor the computers might mistake it for a real obstacle. Then Alice might try backing up to check if the obstacle remained. The Jet Propulsion Laboratory (JPL) uses some of these approaches in building its autonomous rovers to explore other planets' surfaces. "Part of the approach we take is to build on what JPL has been doing for years," Murray says.

The Caltech team consists of almost 80 undergraduate and graduate students, postdocs, and faculty, many of whom participated in the previous Grand Challenge. Specialists from JPL and Northrop Grumman added their expertise. In the final event, the team whose vehicle reaches the finish line first in less than six hours wins $2 million, second place garners $1 million, and third, $500,000.

The public is invited to attend both the qualifying round and the finals, and admission is free for both events, with grandstand seating available. The qualifying round begins with an opening ceremony at 7 a.m. on October 26 and continues through October 31. The finalists will be announced on November 1, with the final round following on November 3. Spectator information is available at the DARPA Grand Challenge website: http://www.darpa.mil/grandchallenge/spectators.asp. For the latest information on Team Caltech, visit its website: http://gc.caltech.edu.

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Elisabeth Nadin
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Caltech Scientists Create Breakthrough Sensor Capable of Detecting Individual Molecules

PASADENA, Calif.- Applied physicists at the California Institute of Technology have figured out a way to detect single biological molecules with a microscopic optical device. The method has already proven effective for detecting the signaling proteins called cytokines that indicate the function of the immune system, and it could be used in numerous medical applications, such as the extremely early detection of cancer and other diseases, as well as in basic biological research.

According to Kerry Vahala, the Jenkins Professor of Information Science and Technology and professor of applied physics, this new detection technology revolves around a previous invention from his lab called an "ultra-high-Q microtoroid resonator." This is a donut-shaped glass device that is narrower than the width of a human hair and that is able to hold on to light very efficiently. Vahala explains that "the detector relies upon this feature to boost sensitivity to the single molecule level, albeit in a surprising way." He notes that the original idea was to detect an optical response elicited directly by molecules landing on the donut-shaped device. "As work proceeded, however, we were able to observe single molecule detection events with far greater ease than was originally expected." This pleasant surprise was traced to minute amounts of heat generated when molecules interact with the light stored within the microtoroid resonator. "This thermo-optic response boosts the sensitivity a millionfold," explains Vahala. Andrea Armani, who works in Vahala's laboratory and developed the detector as part of her thesis research, notes that besides being extremely sensitive, the device is also programmable by coating its surface with substances that react to a specific biological molecule. "The molecule which the device is targeting, whether it is a growth factor or a chemical like TNT, is determined by the surface treatment of the glass microtoroid. Fortunately, the biology and chemistry communities have developed very effective techniques for attaching proteins to glass surfaces, because most microscope slides are glass. All we had to do was adopt those techniques to fit our structure," explains Armani.

Vahala notes that "this combination of single-molecule sensitivity and programmable detection, that is, without labeling of the target molecule, has not been demonstrated before, and enables new kinds of tests and measurement."

Scott Fraser, the Rosen Professor of Biology, professor of bioengineering, and collaborator on the project, explains further that "this technology should lead to many applications for biological experiments, medical tests, and even medical treatments. The advantages are its ability to detect extremely small numbers of molecules, and the fact that there's no need to label target molecules. At this sensitivity level, it is possible even to study growth factors being emitted in real time from a single cell." Fraser adds, "This is the only sensor that currently has the requisite sensitivity and rapidity."

This type of experiment is important in monitoring how environmental changes, such as pH or temperature, can influence a cell's behavior. Currently, these types of experiments must be performed with populations of millions of cells, which often blurs results because it is like trying to pick out a single voice in a choir.

In the July 5 issue of the online journal Science Express, the team reports on its success in detecting a series of different molecules, including one immune response signaling protein, interleukin-2 (IL-2). For the latter, the targeting molecule the devices were coated with was a specific antibody that recognized IL-2. This surface preparation allowed the detector surface to bind the IL-2, while the thermo-optic mechanism provided the sensitivity required to detect the IL-2 at the single molecule level, even in serum (blood with the clotting factors and red blood cells removed).

"What is most exciting about this device is its ability to get single molecule results in real time without labeling. Because it can be programmed to detect almost any biological molecule, it is a universal detector, and as such opens the door to a whole field of new experiments," adds Armani.

The work was supported by the Defense Advanced Research Projects Agency-funded Center for Optofluidic Integration at Caltech.

The coauthors of the paper are Armani, a Clare Boothe Luce postdoctoral fellow; Vahala; Fraser; Richard Flagan, the McCollum-Corcoran Professor of Chemical Engineering and professor of environmental science and engineering; and Rajan Kulkarni, a recent Caltech biology doctoral graduate.

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Robert Tindol
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On-Chip Optics Makes Continuous Visible Light from Low-Power Infrared

PASADENA, Calif.--If you shine a red laser pointer through a glass window you wouldn't expect it to come out blue on the other side, but with a much brighter beam it just might. At high intensities light energy tends to combine and redistribute, so that red light really can produce blue.

It normally takes a lot of power to boost light into this high-intensity realm. Yet two scientists at the California Institute of Technology have found a way to do more with less, producing a continuous beam of visible light from an infrared source with less than a milliwatt of power.

"Usually this is accomplished using very brief, concentrated bursts of light," says Kerry Vahala, the Ted and Ginger Jenkins Professor of Information Science and Technology and professor of applied physics at Caltech. "To be able to do this continuously and at power levels below a milliwatt is remarkable."

Although infrared light is invisible to human eyes, it is essential to modern telecommunications, flowing through millions of miles of optical fiber. Technology to produce, amplify, and otherwise manipulate near-infrared light is well developed and readily available.

Now, Vahala and Tal Carmon, a postdoctoral scholar in applied physics at Caltech, have linked that mature technology right into the center of the visible spectrum. Their work is basic research that could leverage an established technology for new uses. "When we developed this, we knew there were a number of potential applications," Vahala says.

Yet generating continuous visible light from infrared came as a pleasant surprise. Usually researchers in infrared optics can't directly see their results. This time, Carmon says, "I just turned off the lights and you could see the effect immediately."

At high intensities, light enters the regime of nonlinear optics. We usually notice nonlinearity when there gets to be enough of something to change its environment and rewrite the rules. For example, when a freeway is nearly empty and vehicles effectively have the road to themselves, traffic will behave the same way even with twice as many cars. The only difference is that the flow will double, which is a proportional, or linear, response. But once traffic nears peak capacity, the vehicles no longer act independently, and the flow becomes miserably nonlinear.

Similarly, light beams pass right through each other at the low intensities we typically encounter, because the photons that make up the beams can usually ignore the cross traffic. At high intensities, however, photons become much more likely to collide and reassemble into other photons. Picture three Mini Coopers in dense traffic coalescing into an SUV. The big vehicles of the photon world lie at the higher-energy or blue end of the spectrum, with lower-energy photons appearing as red or even infrared light.

Nonlinear optics usually requires brief megawatt intensities, analogous to flooding the freeway with a sudden burst of traffic, but the Caltech researchers employ a different strategy. They achieve their optical congestion from a much smaller flow, by diverting traffic into a tiny no-exit roundabout.

Their traffic circle is a miniscule glass donut, a microresonator smaller across than a human hair. It accumulates power so that a mere milliwatt of infrared light flowing outside the device can sustain an internal flow of 300 watts, an amplification of 300,000. Although infrared light is essentially trapped inside, energy can still escape as visible light, when three infrared photons combine into a single photon of tripled frequency: the third harmonic.

The two researchers describe this work in the Nature Physics article: "Visible Continuous Emission from a Silica Microphotonic Device by Third-Harmonic Generation."

"Our device has several important features," Vahala says. "First it triples the light frequency, and second, it works in a wide range of frequencies. This means full access to the entire visible spectrum, and likely ultraviolet. Right now there isn't a way of doing UV generation on a chip. Tunable ultraviolet-that's exciting." Coherent UV sources have applications in sensing and also data storage where, for example, wavelength determines the physical size of the information bit on a compact disk.

The microresonator is part of a promising approach for on-chip optical devices using the silica-on-silicon platform, which is compatible with the electronics of ordinary computer chips. Integrating optics and electronics on the same chip makes the device useful for lab-on-a-chip designs, and the ability to use established fabrication techniques makes large-scale, low-cost production possible.

Writer: 
JA
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Early Rocketeer Homer Stewart Dies

PASADENA, Calif.—Homer Stewart, an early pioneer of rocket research who helped develop Explorer I, America's first satellite, died Saturday, May 26, at his home in Altadena, California. He was 91.

A native of Dubuque, Iowa, Stewart came to the California Institute of Technology for graduate study in 1936 and became interested in the early pioneering rocket research that was being carried out at the time by a small group of Caltech engineers and scientists, chief among them Theodore von Kármán. Stewart, von Kármán, and others began testing rockets in a rugged foothill area of the San Gabriel Mountains about five miles northeast of the Pasadena campus, thereby forming the nucleus of the research group that would evolve into the Jet Propulsion Laboratory.

In 1938, Stewart joined the Caltech faculty from 1938, teaching both aeronautics and meteorology; but for many years he divided his time between his faculty duties and research at JPL. As chief of the research analysis section, he participated in many rocket projects, including the WAC Corporal, the Corporal, the Sergeant, and the Jupiter C. He was chief of JPL's liquid propulsion systems division when JPL and the Army Ballistic Missile Agency (now the Marshall Space Flight Center) developed and launched Explorer I.

His research interests included rocket exhaust velocity requirements for maintaining the exact trajectories of spacecraft. He also conducted research in wind-driven energy, using his knowledge of fluid flow to construct with von Kármán a turbine in the mountains of Vermont in the late 1930s. The the machine generated up to a megawatt of power and operated through World War II in cooperation with a local electrical company. The project was abandoned after the war, in part because of the easy availability of cheap fossil-fuel energy.

Stewart earned his bachelor's degree at the University of Minnesota in 1936 and his doctorate in aeronautics at Caltech in 1940. He served continuously on the Caltech faculty from 1938 until his retirement in 1980.

He is survived by two daughters, Barbara Mogel of Chesapeake Beach, Maryland, and Kay Stewart of San Diego; a son, Dr. Robert J. Stewart of Burien, Washington; and two grandchildren.

Writer: 
Robert Tindol
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