Caltech Researchers Find Evidence of Link between Immune Irregularities and Autism

PASADENA, Calif.—Scientists at the California Institute of Technology (Caltech) pioneered the study of the link between irregularities in the immune system and neurodevelopmental disorders such as autism a decade ago. Since then, studies of postmortem brains and of individuals with autism, as well as epidemiological studies, have supported the correlation between alterations in the immune system and autism spectrum disorder.

What has remained unanswered, however, is whether the immune changes play a causative role in the development of the disease or are merely a side effect. Now a new Caltech study suggests that specific changes in an overactive immune system can indeed contribute to autism-like behaviors in mice, and that in some cases, this activation can be related to what a developing fetus experiences in the womb.

The results appear in a paper this week in the Proceedings of the National Academy of Sciences (PNAS).

"We have long suspected that the immune system plays a role in the development of autism spectrum disorder," says Paul Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences at Caltech, who led the work. "In our studies of a mouse model based on an environmental risk factor for autism, we find that the immune system of the mother is a key factor in the eventual abnormal behaviors in the offspring."

The first step in the work was establishing a mouse model that tied the autism-related behaviors together with immune changes. Several large epidemiological studies—including one that involved tracking the medical history of every person born in Denmark between 1980 and 2005—have found a correlation between viral infection during the first trimester of a mother's pregnancy and a higher risk for autism spectrum disorder in her child. To model this in mice, the researchers injected pregnant mothers with a viral mimic that triggered the same type of immune response a viral infection would.

"In mice, this single insult to the mother translates into autism-related behavioral abnormalities and neuropathologies in the offspring," says Elaine Hsiao, a graduate student in Patterson's lab and lead author of the PNAS paper. 

The team found that the offspring exhibit the core behavioral symptoms associated with autism spectrum disorder—repetitive or stereotyped behaviors, decreased social interactions, and impaired communication. In mice, this translates to such behaviors as compulsively burying marbles placed in their cage, excessively self grooming, choosing to spend time alone or with a toy rather than interacting with a new mouse, or vocalizing ultrasonically less often or in an altered way compared to typical mice. 

Next, the researchers characterized the immune system of the offspring of mothers that had been infected and found that the offspring display a number of immune changes. Some of those changes parallel those seen in people with autism, including decreased levels of regulatory T cells, which play a key role in suppressing the immune response. Taken together, the observed immune alterations add up to an immune system in overdrive—one that promotes inflammation.

"Remarkably, we saw these immune abnormalities in both young and adult offspring of immune-activated mothers," Hsiao says. "This tells us that a prenatal challenge can result in long-term consequences for health and development."

With the mouse model established, the group was then able to test whether the offspring's immune problems contribute to their autism-related behaviors. In the most revealing test of this hypothesis, the researchers were able to correct many of the autism-like behaviors in the offspring of immune-activated mothers by giving the offspring a bone-marrow transplant from typical mice. The normal stem cells in the transplanted bone marrow not only replenished the immune system of the host animals but altered their autism-like behavioral impairments. 

The researchers emphasize that because the work was conducted in mice, the results cannot be readily extrapolated to humans, and they certainly do not suggest that bone-marrow transplants should be considered as a treatment for autism. They also have yet to establish whether it was the infusion of stem cells or the bone-marrow transplant procedure itself—complete with irradiation—that corrected the behaviors.

However, Patterson says, the results do suggest that immune irregularities in children could be an important target for innovative immune manipulations in addressing the behaviors associated with autism spectrum disorder. By correcting these immune problems, he says, it might be possible to ameliorate some of the classic developmental delays seen in autism.

In future studies, the researchers plan to examine the effects of highly targeted anti-inflammatory treatments on mice that display autism-related behaviors and immune changes. They are also interested in considering the gastrointestinal (GI) bacteria, or microbiota, of such mice. Coauthor Sarkis Mazmanian, a professor of biology at Caltech, has shown that gut bacteria are intimately tied to the function of the immune system. He and Patterson are investigating whether changes to the microbiota of these mice might also influence their autism-related behaviors.

Along with Patterson, Hsiao, and Mazmanian, additional Caltech coauthors on the PNAS paper, "Modeling an autism risk factor in mice leads to permanent immune dysregulation," are Mazmanian lab manager Sara McBride and former graduate student Janet Chow. The work was supported by an Autism Speaks Weatherstone Fellowship, National Institutes of Health Graduate Training Grants, a Weston Havens Foundation grant, a Gregory O. and Jennifer W. Johnson Caltech Innovation Fellowship, a Caltech Innovation grant, and a Congressionally Directed Medical Research Program Idea Development Award. 

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Autism and the Immune System
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A New Kind of Amplifier

Caltech researchers develop instrument for exploring the cosmos and the quantum world

PASADENA, Calif.—Researchers at the California Institute of Technology (Caltech) and NASA's Jet Propulsion Laboratory (JPL) have developed a new type of amplifier for boosting electrical signals. The device can be used for everything from studying stars, galaxies, and black holes to exploring the quantum world and developing quantum computers.

"This amplifier will redefine what it is possible to measure," says Jonas Zmuidzinas, Caltech's Merle Kingsley Professor of Physics, the chief technologist at JPL, and a member of the research team.

An amplifier is a device that increases the strength of a weak signal. "Amplifiers play a basic role in a wide range of scientific measurements and in electronics in general," says Peter Day, a visiting associate in physics at Caltech and a principal scientist at JPL. "For many tasks, current amplifiers are good enough. But for the most demanding applications, the shortcomings of the available technologies limit us." 

Conventional transistor amplifiers—like the ones that power your car speakers—work for a large span of frequencies. They can also boost signals ranging from the faint to the strong, and this so-called dynamic range enables your speakers to play both the quiet and loud parts of a song. But when an extremely sensitive amplifier is needed—for example, to boost the faint, high-frequency radio waves from distant galaxies—transistor amplifiers tend to introduce too much noise, resulting in a signal that is more powerful but less clear.

One type of highly sensitive amplifier is a parametric amplifier, which boosts a weak input signal by using a strong signal called the pump signal. As both signals travel through the instrument, the pump signal injects energy into the weak signal, therefore amplifying it.

About 50 years ago, Amnon Yariv, Caltech's Martin and Eileen Summerfield Professor of Applied Physics and Electrical Engineering, showed that this type of amplifier produces as little noise as possible: the only noise it must produce is the unavoidable noise caused by the jiggling of atoms and waves according to the laws of quantum mechanics. The problem with many parametric amplifiers and sensitive devices like it, however, is that they can only amplify a narrow frequency range and often have a poor dynamic range.

But the Caltech and JPL researchers say their new amplifier, which is a type of parametric amplifier, combines only the best features of other amplifiers. It operates over a frequency range more than ten times wider than other comparably sensitive amplifiers, can amplify strong signals without distortion, and introduces nearly the lowest amount of unavoidable noise. In principle, the researchers say, design improvements should be able to reduce that noise to the absolute minimum. Versions of the amplifier can be designed to work at frequencies ranging from a few gigahertz to a terahertz (1,000 GHz). For comparison, a gigahertz is about 10 times greater than commercial FM radio signals in the U.S., which range from about 88 to 108 megahertz (1 GHz is 1,000 MHz).

"Our new amplifier has it all," Zmuidzinas says. "You get to have your cake and eat it too."

The team recently described the new instrument in the journal Nature Physics.

One of the key features of the new parametric amplifier is that it incorporates superconductors—materials that allow an electric current to flow with zero resistance when lowered to certain temperatures. For their amplifier, the researchers are using titanium nitride (TiN) and niobium titanium nitride (NbTiN), which have just the right properties to allow the pump signal to amplify the weak signal.

Although the amplifier has a host of potential applications, the reason the researchers built the device was to help them study the universe. The team built the instrument to boost microwave signals, but the new design can be used to build amplifiers that help astronomers observe in a wide range of wavelengths, from radio waves to X rays.

For instance, the team says, the instrument can directly amplify radio signals from faint sources like distant galaxies, black holes, or other exotic cosmic objects. Boosting signals in millimeter to submillimeter wavelengths (between radio and infrared) will allow astronomers to study the cosmic microwave background—the afterglow of the big bang—and to peer behind the dusty clouds of galaxies to study the births of stars, or probe primeval galaxies. The team has already begun working to produce such devices for Caltech's Owens Valley Radio Observatory (OVRO) near Bishop, California, about 250 miles north of Los Angeles. 

These amplifiers, Zmuidzinas says, could be incorporated into telescope arrays like the Combined Array for Research in Millimeter-wave Astronomy at OVRO, of which Caltech is a consortium member, and the Atacama Large Millimeter/submillimeter Array in Chile.

Instead of directly amplifying an astronomical signal, the instrument can be used to boost the electronic signal from a light detector in an optical, ultraviolet, or even X-ray telescope, making it easier for astronomers to tease out faint objects.

Because the instrument is so sensitive and introduces minimal noise, it can also be used to explore the quantum world. For example, Keith Schwab, a professor of applied physics at Caltech, is planning to use the amplifier to measure the behavior of tiny mechanical devices that operate at the boundary between classical physics and the strange world of quantum mechanics. The amplifier could also be used in the development quantum computers—which are still beyond our technological reach but should be able to solve some of science's hardest problems much more quickly than any regular computer.

"It's hard to predict what all of the applications are going to end up being, but a nearly perfect amplifier is a pretty handy thing to have in your bag of tricks," Zmuidzinas says. And by creating their new device, the researchers have shown that it is indeed possible to build an essentially perfect amplifier. "Our instrument still has a few rough edges that need polishing before we would call it perfect, but we think our results so far show that we can get there."

The title of the Nature Physics paper is "A wideband, low-noise superconducting amplifier with high dynamic range." In addition to Zmuidzinas and Day, the other authors of the paper are Byeong Ho Eom, an associate research engineer at Caltech, and Henry LeDuc, a senior research scientist at JPL. This research was supported by NASA, the Keck Institute for Space Studies, and the JPL Research and Technology Development program.

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Peering Into the Heart of a Supernova

Caltech simulation points out how to detect a rapidly spinning stellar core

PASADENA, Calif.—Each century, about two massive stars in our own galaxy explode, producing magnificent supernovae. These stellar explosions send fundamental, uncharged particles called neutrinos streaming our way and generate ripples called gravitational waves in the fabric of space-time. Scientists are waiting for the neutrinos and gravitational waves from about 1,000 supernovae that have already exploded at distant locations in the Milky Way to reach us. Here on Earth, large, sensitive neutrino and gravitational-wave detectors have the ability to detect these respective signals, which will provide information about what happens in the core of collapsing massive stars just before they explode.

If we are to understand that data, however, scientists will need to know in advance how to interpret the information the detectors collect. To that end, researchers at the California Institute of Technology (Caltech) have found via computer simulation what they believe will be an unmistakable signature of a feature of such an event: if the interior of the dying star is spinning rapidly just before it explodes, the emitted neutrino and gravitational-wave signals will oscillate together at the same frequency.

"We saw this correlation in the results from our simulations and were completely surprised," says Christian Ott, an assistant professor of theoretical astrophysics at Caltech and the lead author on a paper describing the correlation, which appears in the current issue of the journal Physical Review D. "In the gravitational-wave signal alone, you get this oscillation even at slow rotation. But if the star is very rapidly spinning, you see the oscillation in the neutrinos and in the gravitational waves, which very clearly proves that the star was spinning quickly—that's your smoking-gun evidence."

Scientists do not yet know all the details that lead a massive star—one that is at least 10 times as massive as the Sun—to become a supernova. What they do know (which was first hypothesized by Caltech astronomer Fritz Zwicky and his colleague Walter Baade in 1934) is that when such a star runs out of fuel, it can no longer support itself against gravity's pull, and the star begins to collapse in upon itself, forming what is called a proto-neutron star. They also now know that another force, called the strong nuclear force, takes over and leads to the formation of a shock wave that begins to tear the stellar core apart. But this shock wave is not energetic enough to completely explode the star; it stalls part way through its destructive work.

There needs to be some mechanism—what scientists refer to as the "supernova mechanism"—that completes the explosion. But what could revive the shock? Current theory suggests several possibilities. Neutrinos could do the trick if they were absorbed just below the shock, re-energizing it. The proto-neutron star could also rotate rapidly enough, like a dynamo, to produce a magnetic field that could force the star's material into an energetic outflow, called a jet, through its poles, thereby reviving the shock and leading to explosion. It could also be a combination of these or other effects. The new correlation Ott's team has identified provides a way of determining whether the core's spin rate played a role in creating any detected supernova.

It would be difficult to glean such information from observations using a telescope, for example, because those provide only information from the surface of the star, not its interior. Neutrinos and gravitational waves, on the other hand, are emitted from inside the stellar core and barely interact with other particles as they zip through space at the speed of light. That means they carry unaltered information about the core with them. 

The ability neutrinos have to pass through matter, interacting only ever so weakly, also makes them notoriously difficult to detect. Nonetheless, neutrinos have been detected: twenty neutrinos from Supernova 1987a in the Large Magellanic Cloud were detected in February 1987. If a supernova went off in the Milky Way, it is estimated that current neutrino detectors would be able to pick up about 10,000 neutrinos. In addition, scientists and engineers now have detectors—such as the Laser Interferometer Gravitational-Wave Observatory, or LIGO, a collaborative project supported by the National Science Foundation and managed by Caltech and MIT—in place to detect and measure gravitational waves for the first time.

Ott's team happened across the correlation between the neutrino signal and the gravitational-wave signal when looking at data from a recent simulation. Previous simulations focusing on the gravitational-wave signal had not included the effect of neutrinos after the formation of a proto-neutron star. This time around, they wanted to look into that effect. 

"To our big surprise, it wasn't that the gravitational-wave signal changed significantly," Ott says. "The big new discovery was that the neutrino signal has these oscillations that are correlated with the gravitational-wave signal." The correlation was seen when the proto-neutron star reached high rotational velocities—spinning about 400 times per second.

Future simulation studies will look in a more fine-grained way at the range of rotation rates over which the correlated oscillations between the neutrino signal and the gravitational-wave signal occur. Hannah Klion, a Caltech undergraduate student who recently completed her freshman year, will conduct that research this summer as a Summer Undergraduate Research Fellowship (SURF) student in Ott's group. When the next nearby supernova occurs, the results could help scientists elucidate what happens in the moments right before a collapsed stellar core explodes.

In addition to Ott, other Caltech authors on the paper, "Correlated Gravitational Wave and Neutrino Signals from General-Relativistic Rapidly Rotating Iron Core Collapse," are Ernazar Abdikamalov, Evan O'Connor, Christian Reisswig, Roland Haas, and Peter Kalmus. Steve Drasco of the California Polytechnic State University in San Luis Obispo, Adam Burrows of Princeton University, and Erik Schnetter of the Perimeter Institute for Theoretical Physics in Ontario, Canada, are also coauthors. Ott is an Alfred P. Sloan Research Fellow.

Most of the computations were completed on the Zwicky Cluster in the Caltech Center for Advanced Computing Research. Ott built the cluster with a grant from the National Science Foundation. It is supported by the Sherman Fairchild Foundation.

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New Class of Catalysts Opens Up Green Route to a Range of Chemical Products

Caltech chemists in the lab of Nobel laureate Bob Grubbs have developed a new class of catalysts that will increase the range of chemicals—from pharmaceuticals, insect pheromones, and perfume musks to advanced plastics—that can be synthesized using environmentally friendly methods.

"We have been trying to develop this particular class of catalysts for about 15 years," says Grubbs, the Victor and Elizabeth Atkins Professor of Chemistry at Caltech.

Like the catalysts that earned Grubbs the 2005 Nobel Prize in Chemistry, the new chemicals include the metal ruthenium and help drive a chemical reaction called olefin metathesis. That reaction has proven useful and efficient for making chemical products that involve pairs of carbon atoms connected by double bonds.

"Our original catalysts have found many applications," Grubbs notes, "but one of the deficiencies was the lack of control of the geometry of the double bond."

And, indeed, what sets the new class of catalysts apart is their ability to selectively form products that have a particular geometry.

To understand that geometry, think first of trans fats. Like other fats, trans fats are essentially chains of fatty acids that contain carbon-carbon double bonds. The "trans" refers to the geometry or configuration of groups of atoms with relation to those double bonds—they can be either trans or cis. If the groups of atoms connected to the carbons of the double bond are located kitty-corner to each other, they exist in the trans configuration; if they are on the same side, the bonds are cis double bonds. Natural fats contain cis double bonds. Trans fats are formed during chemical processing, and the unnatural fats have been found to be unhealthy.

In most circumstances, trans double bonds are much more stable than their cis counterparts. Since metathesis is a double-bond forming reaction that tends to form the more stable product, it primarily forms trans double bonds. But there are many compounds that scientists and manufacturers would like to make that include pure cis, rather than trans double bonds. Some desired compounds that contain cis double bonds are pharmaceutical targets; others make it possible to manufacture polymers with enhanced properties.

"People haven't been able to make these cis double bonds using ruthenium-based olefin metathesis before," says Myles Herbert, a graduate student in Grubbs's lab who has been working with the new catalysts. There are alternative methods for making cis double bonds, but the most popular tend to generate a lot of chemical waste, making them less economical and less environmentally friendly than metathesis, which is considered a green chemical reaction.

Herbert has been focusing on one promising application of the new catalysts—using them to synthesize insect pheromones. Insects such as the gypsy moth and the Douglas-fir tussock moth are responsible for massive deforestation around the world, and others destroy acres of crops. Rather than using poisonous pesticides to control such populations, farmers are beginning to attack the problem by spraying their fields with female insect sex pheromones. Male bugs follow pheromones to locate females; raising the concentration of those chemicals effectively overwhelms their senses, so they are unable to find mates.

"These pheromones are all nontoxic, so it would be great if they could be adapted for use on an industrial scale," Herbert says. "Since many of them involve cis double bonds, I'm trying to use the new catalysts and metathesis to find a shorter synthesis that uses cheaper materials to make these pheromones."

A Serendipitous Discovery

The new class of catalysts was discovered largely by chance. Theoretical work by William Goddard III, Caltech's Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics, and his group suggested that one particular catalyst might yield products with cis double bonds. So while visiting Grubbs's lab, Koji Endo, from Mitsui Chemicals in Japan, set about trying to synthesize that catalyst, which was later proven to be ineffective. However, in the process of trying to make that catalyst, Endo happened across a very unusual reaction that produced an entirely unexpected compound, which turned out to be the first in this new class of ruthenium catalysts. 

"We had seen complexes that were reminiscent of this before, but they always decomposed," says Grubbs's graduate student Keith Keitz, a coauthor on several papers published in the past year describing the new class of catalysts. "So it was really surprising to us that, first of all, this was stable, and second, that when Koji threw it in with some of our standard reaction conditions, this catalyst showed an unprecedented selectivity for cis double bonds."

The reaction looked promising, but there was room for improvement. The first-generation catalyst yielded a mix of products containing roughly half cis and half trans double bonds (previously, the best catalysts produced mixtures with 10 times as many compounds with trans double bonds). To convince synthetic chemists to begin regularly using metathesis to create compounds containing cis double bonds, the researchers would need a catalyst that generated cis bonds 80–100% of the time. And the catalyst would need to be reusable, without being used up—that is, have a high turnover number. Endo's first catalyst had a turnover number around 50. It also tended to decompose in solution within about two hours of being exposed to air; an ideal catalyst would be stable in solution or even on the bench top for days at a time.

The Grubbs team has now made several versions of the catalyst and found one that can be used at least 1,000 times and is much more stable than the original. "We can expose a solution of this to oxygen, and it will stay alive for more than 12 hours," Keitz says. "If you just take a vial of this powder and leave it on the bench, it will be good for over 10 days."

Going forward, the researchers hope to use the new catalysts to synthesize large chemical rings, or macrocycles. Macrocycles are common in chemical fragrances (particularly musks) and are found in pharmaceuticals used to treat cancer and other diseases. Previous metathesis catalysts have been used to create trans macrocycles for these purposes, but the catalysts could not make rings that had a high cis double bond content. "We're hoping that our new catalysts will make it possible to synthesize these compounds using metathesis—a proven green reaction," says Grubbs.

Over the past year and a half, the Grubbs group has published several papers in the Journal of the American Chemical Society about these new catalysts. The work is financially supported by the National Science Foundation, the National Institutes of Health, Mitsui Chemicals, Inc., the Department of Defense, and the Swiss National Science Foundation.

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New Class of Catalysts Has Green Possibilities
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Physicists Discover a New Particle that May Be the Higgs Boson

International consortium of scientists includes a large Caltech contingent

PASADENA, Calif.—Physicists at the Large Hadron Collider (LHC) in Geneva, Switzerland, have discovered a new particle that may be the long-sought Higgs boson, the fundamental particle that is thought to endow elementary particles with mass. 

"This is a momentous time in the history of particle physics and in scientific exploration—the implications are profound," says Harvey Newman, professor of physics at the California Institute of Technology (Caltech). "This is experimental science at its best."

The international team of scientists and engineers—which includes a large contingent from Caltech, led by Newman and Maria Spiropulu, professor of physics—says it needs more data to determine for certain if the particle they've discovered is indeed the Higgs boson predicted by the Standard Model, the theory that describes how all particles interact. The results so far, however, show that it has many of the properties expected for such a particle. 

"One of the most exciting aspects of this observation is that the road remains open for a vast range of 'lookalike' alternatives, where any deviation from the Standard Model would point the way to the existence of other new particles or forces of nature," Newman says.

Regardless of the exact identity of the new particle, CERN's scientists say, the highly anticipated discovery heralds a new era in physics.

The physicists revealed their latest results at a seminar at the European Center for Nuclear Research (CERN) in Geneva, which was shared with the world with a live webcast and the EVO (Enabling Virtual Organizations) system developed at Caltech.

The discovery itself is based on the analysis of an unprecedented amount of data that was collected by the two main detectors at the LHC—the Compact Muon Solenoid (CMS) and A Toroidal LHC Apparatus (ATLAS). The data was collected with the LHC running at 7 teraelectron volts (TeV, a unit of energy) in 2011 and 8 TeV in 2012. The Caltech team is part of the CMS collaboration.

Using the CMS detector, the physicists identified signals that point to a new particle with a mass of 125 gigaelectron volts (GeV, a unit of mass; in comparison, the mass of a proton is about 1 GeV). The team running the ATLAS detector, which searches for the Higgs using a different method, reported similar results.

"This is an incredible, exciting moment," says Spiropulu. "Even these early results give us important hints as to how mass in the universe came to be. Together with hundreds of our colleagues Caltech scientists have worked for decades to reach this point: building multiple generations of experiments; designing and building detectors to precisely measure photons, electrons, and muons, which are keys to the discovery; and inventing worldwide systems that empower thousands of physicists throughout the world to collaborate day and night, share and analyze the data, and develop the new techniques leading to this great result."

To search for the Higgs, physicists have had to comb through the remains of trillions of particle collisions produced by the LHC, which accelerates protons around a ring almost five miles wide to nearly the speed of light. As the protons careen toward each other, a small fraction of them collide, creating other particles such as the Higgs. It is estimated that it takes one billion collisions to make just one Higgs boson.

The Higgs is fleeting, however, and quickly decays into lighter particles, which are the traces that allow the Higgs to be detected and analyzed. The Higgs is predicted to decay in several different ways, or channels, each resulting in different particles. CMS focuses mainly on the decay channels that result in two photons or two other particles called Z bosons. It was by measuring and analyzing these and other decay particles that the physicists were able to discover the potential Higgs.

When all the decays are taken into account in combination, the scientists announced, the data for a signal corresponding to a Standard Model Higgs boson have a statistical significance of five sigmas. This means the signal is highly unlikely to be the result of a statistical fluke caused by some rare, background fluctuation. Only when data are significant to five sigmas are physicists confident enough to declare a discovery.

Last December, evidence seen in the data from CMS generated plenty of excitement as a result of an excess of events—a slight surplus in particle collision events over what would have been expected if the Higgs does not exist—with a statistical significance of just three sigmas.

The Higgs boson is the last remaining fundamental particle predicted by the Standard Model yet to be detected, and hopes of detecting it was one of the chief reasons for building the LHC. The LHC accelerator, along with the CMS and ATLAS experiments, are arguably the largest and most complex scientific instruments ever built.

Despite its many successes, the Standard Model is incomplete—it does not incorporate gravity or dark matter, for example. One of the goals of physicists, then, is to develop more complete theories that better explain the composition of the universe and what happened during the first moments after the Big Bang. Discovering the Higgs boson—or a particle like it—is essential for developing these new theories.

The measurements of the new particle, the physicists say, are so far consistent—within statistical uncertainty—with the Higgs boson as predicted by the Standard Model. Still, they need more data to know for sure whether it is the predicted Higgs or something stranger, a Higgs lookalike—a prospect that many theorists have long been anticipating.  

By the end of 2012, the Caltech researchers say, the CMS collaboration expects to more than double its current total amount of data. With more data and analysis, the scientists might then be able to confirm whether the particle they announced is indeed the Higgs—and whether it is the Standard Model Higgs or a more exotic version.

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Caltech at the LHC

Maria Spiropulu and Harvey Newman, both professors of physics at Caltech, lead the Caltech team of 40 physicists, students, and engineers that is part of the Compact Muon Solenoid (CMS) collaboration at the Large Hadron Collider (LHC) in Geneva, Switzerland.

Spiropulu is an expert on devising ways to discover exotic phenomena beyond the Standard Model—the theory that describes how all particles interact—such as theories of supersymmetry that predict particles of dark matter. Newman did much of the design and development work on the crystal detectors that are now used in CMS. He also conceived and developed the worldwide grid of networks and data centers that stores and processes the flood of data coming from the LHC. With the LHC generating gigabytes of data per second, no single site can hold all the information, so the data is handled in a distributed fashion at hundreds of sites throughout the world, including Caltech's Center for Advanced Computing Research, the first university-based center for LHC data analysis.

Newman's team also runs the transatlantic network that links the LHC to the United States, allowing data to flow between Europe and North America. His team, together with Steven Low, professor of computer science and electrical engineering at Caltech, developed the state-of-the-art applications for transferring data over long distances, enabling terabytes of data to stream between sites at speeds of up to the 100 gigabits per second. Newman and Caltech engineer Philippe Galvez also developed a system called Enabling Virtual Organizations, an internet-based tool that helps physicists and scientists from other fields communicate and collaborate from anywhere in the world. 

According to Newman and Spiropulu, the Caltech team consists of experts in everything from the detector and data analysis to how new phenomena might manifest at the LHC. Because the group is involved in so many aspects of CMS, Caltech is making a particularly significant contribution, Spiropulu says.

"Caltech is a premier institute of technology," Newman adds. "We continue to use our skills and vision to develop and deploy unique technologies with global impact even as we empower the scientists in our field." 

The Higgs boson is predicted to decay in different ways. The Caltech team is analyzing the data from three of these so-called decay channels: the photon-photon channel, in which the Higgs decays into two photons; the ZZ channel, in which it decays into two particles called Z bosons; and the WW channel, in which the Higgs decays into two particles called W bosons.

Graduate students Yong Yang, Jan Veverka, and Vladlen Timciuc are all studying the photon-photon channel, searching for the Standard Model Higgs and excluding possible imposters. "We make sure CMS precisely measures the energies of photons, electrons, and positrons," says Adi Bornheim, a Caltech staff scientist who led the electromagnetic calorimeter (ECAL) detector group at CMS and currently participates in tests of the signal robustness at 125 gigaelectron volts (GeV, a unit of mass) in the photon-photon channel. Composed of 76,000 crystal detectors and weighing in at more than 90 tons, the calorimeter measures the energy of the electrons and photons produced by LHC collisions with high precision 

Since 1994, Newman and Ren-Yuan Zhu, Caltech's manager of ECAL—along with a team of experts on crystal calorimetry and lasers—have been making sure the detector is calibrated to provide the exquisitely precise measurements required for discovery by the CMS detector. Marat Gataullin, an assistant scientist at Caltech and leader of the calibration team at CMS, says, "It would have been impossible to find the new particle in this channel without the 17-year investment in this special detector of the Caltech CMS group."

Caltech Tolman Fellow Artur Apresyan joined the search in the photon-photon channel recently, along with graduate student Cristian Pena, who recently arrived at CERN (the European Organization for Nuclear Research, the site of the LHC) to carry out the calibration of the ECAL for the remainder of the extended 2012 run. "This is intense," Pena says. "I want to get my hands into the work and contribute immediately."

Another Caltech Tolman Fellow, Emanuele Di Marco, helped lead the analysis of Higgs decays in the WW channel for the CMS team. He will present the results on behalf of CMS at the ICHEP 2012 conference, which will be held from July 4 through 11 in Melbourne, Australia. "As the impact of the discovery sinks in, I realize how much work remains to build the full picture," Di Marco says. "Squeezing the signal out of the WW channel is challenging."   

In addition to the WW channel, Di Marco and newly arrived Caltech Millikan Fellow Si Xie have also worked on the ZZ channel. "We are doing our best to advance CMS's ability to measure this channel," Xie says. "There are already outstanding analysis techniques in CMS and we want to perfect them."

Newman, Spiropulu, Xie, Di Marco, and graduate students Chris Rogan and Yi Chen—in collaboration with colleagues from CERN, Fermilab, and Johns Hopkins University—will continue the preparatory studies for the ZZ channel; they published the first of those studies in the journal Physical Review D in 2010. They developed a kind of Higgs look-alike program that is being applied to the data to pick out the newly discovered particle.

"We will pin down the properties of this new particle," says Rogan, who was honored by Forbes Magazine as one of this year's top 30 leaders in science and technology under 30 years old. "We can learn more—we must use the knowledge from this discovery to inform and help direct our searches for supersymmetry or other exotic forms of new physics as well as experimental searches for dark matter. The implications for many other subfields are very significant." For instance, Javier Mauricio Duarte, a first year graduate student, will be using these findings in his work on supersymmetry and models of dark matter. 

As the LHC continues to ramp up its energy, physicists hope that even more discoveries are on the way. "The LHC is pretty close to my dream experiment, and the LHC at twice the energy will be even better!" said graduate student Alexander Mott in an interview with Scientific American.

Undergraduates are also a critical part of the team. In the last two years, there have been a total of 24 students from the Summer Undergraduate Research Fellowships (SURF) and Minority Undergraduate Research Fellowships (MURF) programs, as well as from programs at CERN. "Caltech students can really 'do things' from an early stage in their careers—at a level one rarely sees elsewhere," Newman says.

This summer, the group includes seven undergraduates (SURFs as well as Rose Hill and Musk Foundation summer fellows) and a couple of CERN summer students. Lisa Lee, a junior at Caltech who just arrived at CERN, sums up the experience so far with a sense of wonder. "What are the chances," she says, "that you take on a summer undergraduate research project in an experiment that makes the most significant discovery in recent history right at the moment you start?"  

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X-ray Telescope Takes First Image

NASA's NuSTAR space telescope has taken its first image, snapping a shot of the high-energy X rays from a black hole in the constellation Cygnus. NuSTAR—short for Nuclear Spectroscopic Telescope Array—was launched on June 13, and is the first telescope that can focus high-energy X rays. It will explore black holes, the dense remnants of dead stars, energetic cosmic explosions, and even our very own sun.

"Today, we obtained the first-ever focused images of the high-energy X-ray universe," says Fiona Harrison, a professor of physics and astronomy at Caltech and the mission's principal investigator, in a NASA press release. "It's like putting on a new pair of glasses and seeing aspects of the world around us clearly for the first time."

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Marcus Woo
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Zooming in on Single Cells

A Caltech chemist improves imaging technology with the help of an NIH award

Last fall, assistant professor of chemistry Long Cai received a New Innovator Award from the National Institutes of Health (NIH)—funding meant to both stimulate highly innovative research and support promising new investigators. Now, just nine months later, Cai has published the first results of his supported research.   

The New Innovator Award is one of the NIH Director's Awards, administered through the organization's Common Fund. The fund provides support for biomedical research deemed to be both innovative and risky.

Cai and his colleagues are working to use high-powered microscopy to help them better understand the genetic programs in individual cells. "We developed a new technique to show that super-resolution microscopy (SRM)—which is a cool, single-molecule-based technology that has been used to zoom in on structures and organelles in cells—can also be used to look at genetic information within a cell, like RNA and proteins," says Cai, who joined the Caltech faculty in 2010.

His paper, "Single-cell systems biology by super-resolution imaging and combinatorial labeling," is available as an advance online publication of the journal Nature Methods.

With the help of coauthor Eric Lubeck, a graduate student in biochemistry and molecular biophysics, Cai labeled individual mRNA molecules within a cell with distinct molecular barcodes. When the cell is imaged using SRM, the barcodes can be resolved and used to read the gene expression levels.   

"If you want to look at a genetic network, then you want to look at many of the individual genes at the same time—this is a way to allow you to do that in single cells," says Cai. "This technique may provide valuable information about rogue cells that are involved in cancer and other diseases, and look at gene expression in single cells within their native environments."

He says that the idea was sparked after a discussion with Barbara Wold, Bren Professor of Biology, about transcription regulation and new advances in single- molecule techniques. "It's really great to have ideas stimulated from an afternoon discussion over coffee," says Cai, "and this is part of what makes Caltech special." The project was started nearly three years ago, when Cai was a Beckman Fellow in the laboratory of Michael Elowitz, professor of biology and a Howard Hughes Medical Institute investigator. "Michael was very generous in letting me use his microscopes and lab to start the experiment," he says. "The NIH award helped us to finish the work when I set up my own lab."

Cai explains that their new method combines two existing technologies. In their proof-of-principle study, the duo was able to measure mRNA molecules in 32 genes simultaneously and within the same cell.   

"Now we're trying to show that it is possible to look at 100 genes at the same time," says Cai, who thinks it will be possible to measure thousands of genes concurrently. "It's just a matter of time."  

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Katie Neith
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The Physics of Going Viral

Caltech researchers measure the rate of DNA transfer from viruses to bacteria

PASADENA, Calif.—Researchers at the California Institute of Technology (Caltech) have been able, for the first time, to watch viruses infecting individual bacteria by transferring their DNA, and to measure the rate at which that transfer occurs. Shedding light on the early stages of infection by this type of virus—a bacteriophage—the scientists have determined that it is the cells targeted for infection, rather than the amount of genetic material within the viruses themselves, that dictate how quickly the bacteriophage's DNA is transferred.

"The beauty of our experiment is we were able to watch individual viruses infecting individual bacteria,"says Rob Phillips, the Fred and Nancy Morris Professor of Biophysics and Biology at Caltech and the principal investigator on the new study. "Other studies of the rate of infection have involved bulk measurements. With our methods, you can actually watch as a virus shoots out its DNA."

The new methods and results are described in a paper titled "A Single-Molecule Hershey–Chase Experiment," which will appear in the July 24 issue of the journal Current Biology and currently appears online. The lead authors of that paper, David Van Valen and David Wu, completed the work while graduate students in Phillips's group.

In the well-known 1952 Hershey-Chase experiment, Alfred Hershey and Martha Chase of the Carnegie Institution of Washington in Cold Spring Harbor convincingly confirmed earlier claims that DNA—and not protein—was the genetic material in cells. To prove this, the researchers used bacteriophages, which are able to infect bacteria using heads of tightly bundled DNA coated in a protein shell. Hershey and Chase radiolabeled sulfur, contained in the protein shell but not in the DNA, and phosphorous, found in the DNA but not in the protein shell. Then they let the bacteriophages infect the bacterial cells. When they isolated the cells and analyzed their contents, they found that only the radioactive phosphorous had made its way into the bacteria, proving that DNA is indeed the genetic material. The results also showed that, unlike the viruses that infect humans, bacteriophages transmit only their genetic information into their bacterial targets, leaving their "bodies" behind.

"This led, right from the get-go, to people wondering about the mechanism—about how the DNA gets out of the virus and into the infected cell," Phillips says. Several hypotheses have focused on the fact that the DNA in the virus is under a tremendous amount of pressure. Indeed, previous work has shown that the genetic material is under more pressure within its protein shell than champagne experiences in a corked bottle. After all, as Phillips says, "There are 16 microns of DNA inside of a tiny 0.05 micron-sized shell. It's like taking 500 meters of cable from the Golden Gate Bridge and putting it in the back of a FedEx truck." 

Phillips's group wanted to find out whether that pressure plays a dominant role in transferring the DNA. Instead, he says, "What we discovered is that the thing that mattered most was not the pressure in the bacteriophage, but how much DNA was in the bacterial cell."

The researchers used a fluorescent dye to stain the DNA of two mutants of a bacteriophage known as lambda bacteriophage—one with a short genome and one with a longer genome—while that DNA was still inside the phage. Using a fluorescence microscope, they traced the glowing dye to see when and over what time period the viral DNA transferred from each phage into an E. coli bacterium. The mean ejection time was about five minutes, though that time varied considerably.

This was markedly different from what the group had seen previously when they ran a similar experiment in a test tube. In that earlier setup, they had essentially tricked the bacteriophages into ejecting their DNA into solution—a task that the phages completed in less than 10 seconds. In that case, once the phage with the longer genome had released enough DNA to make what remained inside the phage equal in length to the shorter genome, the two phages ejected DNA at the same rate. Therefore, Phillips's team reasoned, it was the amount of DNA in the phage that determined how quickly the DNA was transferred.

But Phillips says, "What was true in the test tube is not true in the cell." E. coli cells contain roughly 3 million proteins within a box that is roughly one micron on each side. Less than a hundredth of a micron separates each protein from its neighbors. "There's no room for anything else," Phillips says. "These cells are really crowded." 

And so, when the bacteriophages try to inject their DNA into the cells, the factor that limits the rate of transfer is how jam-packed those cells are. "In this case," Phillips says, "it had more to do with the recipient, and less to do with the pressure that had built up inside the phage."

Looking toward the future, Phillips is interested in using the methods he and his team have developed to study different types of bacteriophages. He also wants to investigate various molecules that could be helping to actively pull the viral DNA into the cells. In the case of a bacteriophage called T7, for instance, previous work has shown that the host cell actually grabs onto the DNA and begins making copies of its genes before the virus has even delivered all the DNA into the cell. "We're curious whether that kind of mechanism is in play with the lambda bacteriophage," Phillips says.

The current findings have implications for the larger question of how biomolecules like DNA and proteins cross membranes in general, and not just into bacteria. Cells are full of membranes that divide them into separate compartments and that separate entire cells from the rest of the world. Much of the business of cellular life involves getting molecules across those barriers. "This process that we've been studying is one of the most elementary examples of what you could call polymer translocation or getting macromolecules across membranes," Phillips says. "We are starting to figure out the physics behind that process."

In addition to Phillips, Van Valen, and Wu, the other authors on the Current Biology paper are graduate student Yi-Ju Chen; Hannah Tuson of the University of Wisconsin at Madison; and Paul Wiggins of the University of Washington. Van Valen is currently a medical student at UCLA's David Geffen School of Medicine, and Wu is an intern at the University of Chicago. The work was supported by funding from the National Science Foundation, a National Institutes of Health Medical Scientist Training Program fellowship, a Fannie and John Hertz Yaser Abu-Mostafa Graduate Fellowship, and an NIH Director's Pioneer Award.

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Seeing Inside Tissue

Caltech researchers develop technique to focus light inside biological tissue

PASADENA, Calif.—Imagine if doctors could perform surgery without ever having to cut through your skin. Or if they could diagnose cancer by seeing tumors inside the body with a procedure that is as simple as an ultrasound. Thanks to a technique developed by engineers at the California Institute of Technology (Caltech), all of that may be possible in the not-so-distant future.

The new method enables researchers to focus light efficiently inside biological tissue. While the previous limit for how deep light could be focused was only about one millimeter, the Caltech team is now able to reach two and a half millimeters. And, in principle, their technique could focus light as much as a few inches into tissue. The technique is used much like a flashlight shining on the body's interior, and may eventually provide researchers and doctors with a host of possible biomedical applications, such as a less invasive way of diagnosing and treating diseases.

If you crank up the power of light, you might even be able to do away with a traditional scalpel. "It enables the possibilities of doing incision-less surgery," says Changhuei Yang, a professor of electrical engineering and bioengineering at Caltech and a senior author on the new study. "By generating a tight laser-focus spot deep in tissue, we can potentially use that as a laser scalpel that leaves the skin unharmed."

Ying Min Wang, a graduate student in electrical engineering, and Benjamin Judkewitz, a postdoctoral scholar, are the lead authors on the paper, which was published in the June 26 issue of the journal Nature Communications.

The new work builds on a previous technique that Yang and his colleagues developed to see through a layer of biological tissue, which is opaque because it scatters light. In the previous work, the researchers shined light through the tissue and then recorded the resulting scattered light on a holographic plate. The recording contained all the information about how the light beam scattered, zigzagging through the tissue. By playing the recording in reverse, the researchers were able to essentially send the light back through to the other side of the tissue, retracing its path to the original source. In this way, they could send light through a layer of tissue without the blurring effect of scattering.

But to make images of what is inside tissue—to get a picture of cells or molecules that are embedded inside, say, a muscle—the researchers would have to be able to focus a light beam into the tissue. "For biologists, it's most important to know what's happening inside the tissue," Wang says.

To focus light into tissue, the researchers expanded on the recent work of Lihong Wang's group at Washington University in St. Louis (WUSTL); they had developed a method to focus light using the high-frequency vibrations of ultrasound. The WUSTL group took advantage of two properties of ultrasound. First, the high-frequency sound waves are not scattered by tissue, which is why it is great for taking images of fetuses in utero. Second, ultrasonic vibrations interact with light in such a way that they shift the light's frequency ever so slightly. As a result of this so-called acousto-optic effect, any light that has interacted with ultrasound changes into a slightly different color.

In both the WUSTL and Caltech experiments, the teams focused ultrasound waves into a small region inside a tissue sample. They then shined light into the sample, which, in turn, scattered the light. Because of the acousto-optic effect, any of the scattered light that passes through the region with the focused ultrasound will change to a slightly different color. The researchers can pick out this color-shifted light and record it. By employing the same playback technique as in the earlier Caltech work, they then send the light back, having only the color-shifted bits retrace their path to the small region where the ultrasound was focused—which means that the light itself is focused on that area, allowing an image to be created. The researchers can control where they want to focus the light simply by moving the ultrasound focus.

The WUSTL experiment was limited, however, because only a very small amount of light could be focused. The Caltech engineers' new method, on the other hand, allows them to fire a beam of light with as much power as they want—which is essential for potential applications. 

The team demonstrated how the new method could be used with fluorescence imaging—a powerful technique used in a wide range of biological and biomedical research. The researchers embedded a patch of gel with a fluorescent pattern that spelled out "CIT" inside a tissue sample. Then, they scanned the sample with focused light beams. The focused light hit and excited the fluorescent pattern, resulting in the glowing letters "CIT" emanating from inside the tissue. The team also demonstrated their technique by taking images of tumors tagged with fluorescent dyes.

"This demonstration that we can focus significant optical power deep within tissues opens up significant possibilities in optical imaging," Yang says. By tagging cells or molecules that are markers for disease with fluorescent dyes, doctors can use this technique to make diagnoses noninvasively, much as if they were doing an ultrasound procedure.

Doctors might also use this process to treat cancer with photodynamic therapy. In this procedure, a drug that contains light-sensitive, cancer-killing compounds is injected into a patient. Cancer cells absorb those compounds preferentially, so that the compounds kill the cells when light shines on them. Photodynamic therapy is now only used at tissue surfaces, because of the way light is easily scattered. The new technique should allow doctors to reach cancer cells deeper inside tissue.

The team has been able to more than double the current limit for how far light can be focused into tissue. With future improvements on the optoelectronic hardware used to record and play back light, the engineers say, they may be able to reach 10 centimeters (almost 4 inches)—the depth limit of ultrasound—within a few years.

Still, the researchers say, their demonstration shows they have overcome the main conceptual hurdle for effectively focusing light deep inside tissue. "This is a big breakthrough, and we're excited about the potential," Judkewitz says. Adds Caltech's Wang, "It's a very new way to image into tissue, which could lead to a lot of promising applications."

The Nature Communications paper is titled "Deep-tissue focal fluorescence imaging with digitally time-reversed ultrasound-encoded light." In addition to Wang, Judkewitz, and Yang, the other author on the paper is Charles DiMarzio of Northeastern University. This work was supported by the National Institutes of Health, the Defense Advanced Research Projects Agency, the Sir Henry Wellcome Postdoctoral Fellowship from the Wellcome Trust, and the National Science Scholarship from the Agency for Science, Technology, and Research in Singapore.

Written by Marcus Woo

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