Growing Unknown Microbes One by One

A new technique developed at Caltech helps grow individual species of the unknown microbes that live in the human body.

Trillions of bacteria live in and on the human body; a few species can make us sick, but many others keep us healthy by boosting digestion and preventing inflammation. Although there's plenty of evidence that these microbes play a collective role in human health, we still know very little about most of the individual bacterial species that make up these communities. Employing the use of a specially designed glass chip with tiny compartments, Caltech researchers now provide a way to target and grow specific microbes from the human gut—a key step in understanding which bacteria are helpful to human health and which are harmful.

The work was published the week of June 23 in the Proceedings of the National Academy of Sciences.

Although a few bacterial species are easy to grow in the laboratory, needing only a warm environment and plenty of food to multiply, most species that grow in and on the human body have never been successfully grown in lab conditions. It's difficult to recreate the complexity of the microbiome—the entire human microbial community—in one small plate (a lidded dish with nutrients used to grow microbes), says Rustem Ismagilov, Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering at Caltech.

There are thousands of species of microbes in one sample from the human gut, Ismagilov says, "but when you grow them all together in the lab, the faster-growing bacteria will take over the plate and the slow-growing ones don't have a chance—leading to very little diversity in the grown sample." Finding slow-growing microbes of interest is like finding a needle in a haystack, he says, but his group wanted to work out a way to "just grow the needle without growing the hay."

To do this, Liang Ma, a postdoctoral scholar in Ismagilov's lab, developed a way to isolate and cultivate individual bacterial species of interest. He and his colleagues began by looking for bacterial species that contained a set of specific genetic sequences. The targeted gene sequences belong to organisms on the list of "Most Wanted" microbes—a list developed by the National Institutes of Health (NIH) Human Microbiome Project. The microbes carrying these genetic sequences are found abundantly in and on the human body, but have been difficult to grow in the lab.

To grow these elusive microbes, the Caltech researchers turned to SlipChip, a microfluidic device previously developed in Ismagilov's lab. SlipChip is made up of two glass slides, each the size of a credit card, that have tiny etched grooves which become channels when the grooved surfaces are stacked atop one another. When a sample—say, a jumbled-up assortment of bacteria species collected from a colonoscopy biopsy—is added to the interconnected channels of the SlipChip, a single "slip" of the top chip will turn the channels into individual wells, with each well ideally holding a single microbe. Once sequestered in an isolated well, each individual bacterium can divide and grow without having to compete for resources with other types of faster-growing microbes.

The researchers then needed to determine which compartment of the SlipChip contained a colony of the target bacterium—which is not a simple task, says Ismagilov. "It's a Catch-22—you have to kill the organism in order to find its DNA sequence and figure out what it is, but you want a live organism at the end of the day, so that you can grow and study this new microbe," he says. "Liang solves this in a really clever way; he grows a compartment full of his target microbe in the SlipChip, then he splits the compartment in half. One half contains the live organism and the other half is sacrificed for its DNA to confirm that the sequence is that of the target microbe."

The method of creating two halves in each well in the SlipChip will be published separately in an upcoming issue of the journal Integrative Biology.

To validate the new methodology, the researchers isolated one specific bacterium from the Human Microbiome Project's "Most Wanted" list. The investigators used the SlipChip to grow this bacterium in a tiny volume of the washing fluid that was used to collect the gut bacteria sample from a volunteer. Since bacteria often depend on nutrients and signals from the extracellular environment to support growth, the substances from this fluid were used to recreate this environment within the tiny SlipChip compartment—a key to successfully growing the difficult organism in the lab.

After growing a pure culture of the previously unidentified bacterium, Ismagilov and his colleagues obtained enough genetic material to sequence a high-quality draft genome of the organism. Although a genomic sequence of the new organism is a useful tool, further studies are needed to learn how this species of microbe is involved in human health, Ismagilov says.

In the future, the new SlipChip technique may be used to isolate additional previously uncultured microbes, allowing researchers to focus their efforts on important targets, such as those that may be relevant to energy applications and the production of probiotics. The technique, says Ismagilov, allows researchers to target specific microbes in a way that was not previously possible.

The paper is titled "Gene-targeted microfluidic cultivation validated by isolation of a gut bacterium listed in Human Microbiome Project's Most Wanted taxa." In addition to Liang and Ismagilov, other coauthors include, from Caltech, associate scientist Mikhail A. Karymov, graduate student Jungwoo Kim, and postdoctoral scholar Roland Hatzenpichler, and, from the University of Chicago department of medicine, Nathanial Hubert, Ira M. Hanan, and Eugene B. Chang. The work was funded by NIH's National Human Genome Research Institute. Microfluidic technologies developed by Ismagilov's group have been licensed to Emerald BioStructures, RanDance Technologies, and SlipChip Corporation, of which Ismagilov is a cofounder.

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Earth-Building Bridgmanite

Our planet's most abundant mineral now has a name

Deep below the earth's surface lies a thick, rocky layer called the mantle, which makes up the majority of our planet's volume. For decades, scientists have known that most of the lower mantle is a silicate mineral with a perovskite structure that is stable under the high-pressure and high-temperature conditions found in this region. Although synthetic examples of this composition have been well studied, no naturally occurring samples had ever been found in a rock on the earth's surface. Thanks to the work of two scientists, naturally occurring silicate perovskite has been found in a meteorite, making it eligible for a formal mineral name.

The mineral, dubbed bridgmanite, is named in honor of Percy Bridgman, a physicist who won the 1946 Nobel Prize in Physics for his fundamental contributions to high-pressure physics.

"The most abundant mineral of the earth now has an official name," says Chi Ma, a mineralogist and director of the Geological and Planetary Sciences division's Analytical Facility at Caltech.

"This finding fills a vexing gap in the taxonomy of minerals," adds Oliver Tschauner, an associate research professor at the University of Nevada-Las Vegas who identified the mineral together with Ma.

High-pressure and temperature experiments, as well as seismic data, strongly suggest that (Mg,Fe)SiO3-perovskite—now simply called bridgmanite—is the dominant material in the lower mantle. But since it is impossible to get to the earth's lower mantle, located some 400 miles deep within the planet, and rocks brought to the earth's surface from the lower mantle are exceedingly rare, naturally occurring examples of this material had never been fully described.

That is until Ma and Tschauner began poking around a sample from the Tenham meteorite, a space rock that fell in Australia in 1879.

Because the 4.5 billion-year-old meteorite had survived high-energy collisions with asteroids in space, parts of it were believed to have experienced the high-pressure conditions we see in the earth's mantle. That, scientists thought, made it a good candidate for containing bridgmanite.

Tschauner used synchrotron X-ray diffraction mapping to find indications of the mineral in the meteorite. Ma then examined the mineral and its surroundings with a high-resolution scanning electron microscope and determined the composition of the tiny bridgmanite crystals using an electron microprobe. Next, Tschauner analyzed the crystal structure by synchrotron diffraction. After five years and multiple experiments, the two were finally able to gather enough data to reveal bridgmanite's chemical composition and crystal structure.

"It is a really cool discovery," says Ma. "Our finding of natural bridgmanite not only provides new information on shock conditions and impact processes on small bodies in the solar system, but the tiny bridgmanite found in a meteorite could also help investigations of phase transformation mechanisms in the deep Earth. "

The mineral and the mineral name were approved on June 2 by the International Mineralogical Association's Commission on New Minerals, Nomenclature and Classification. 

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Katie Neith
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Surprising Results from Game Theory Studies

If you're trying to outwit the competition, it might be better to have been born a chimpanzee, according to a study by researchers at Caltech, which found that chimps at the Kyoto University Primate Research Institute consistently outperform humans in simple contests drawn from game theory.

The study, led by Colin Camerer, Robert Kirby Professor of Behavioral Economics, and appearing on June 5 in the online publication Scientific Reports, involved a simple game of hide-and-seek that researchers call the Inspection Game. In the game, two players (either a pair of chimps or a pair of humans) are set up back to back, each facing a computer screen. To start the game, each player pushes a circle on the monitor and then selects one of two blue boxes on the left or right side of the screen. After both players have chosen left or right, the computer shows each player her opponent's choice. This continues through 200 iterations per game. The goal of the players in the "hiding" role—the "mismatchers"—is to choose the opposite of their opponent's selection. Players in the "seeking" role—the "matchers"—win if they make the same choices as their opponent. Winning players receive a reward: a chunk of apple for the chimps or a small coin for the humans. If players are to win repeatedly, they have to accurately predict what their opponent will do next, anticipating their strategy.

The game, though simple, replicates a situation that is common in the everyday lives of both chimps and humans. Study coauthor Peter Bossaerts, a visiting associate in finance at Caltech, gives an example from human life: an employee who wants to work only when her employer is watching and prefers to play video games when unobserved. To better conceal her secret video game obsession, the employee must learn the patterns of the employer's behavior—when they might or might not be around to check up on the worker. Employers who suspect their employees are up to no good, however, need to be unpredictable, popping in randomly to see what the staff is doing on company time.

The Inspection Game not only models such situations, it also provides methods to quantify behavioral choices. "The nice thing about the game theory used in this study is that it allows you to boil down all of these situations to their strategic essence," explains Caltech graduate student and coauthor Rahul Bhui.

However cleverly you play the Inspection Game, if your opponent is also playing strategically, there is a limit to how often you can win. That limit, many game theorists agree, is best described by the Nash equilibrium, named for mathematician John Forbes Nash Jr., winner of the 1994 Nobel Memorial Prize in Economic Sciences, whose life and career provided the inspiration for the Academy Award–winning 2001 film A Beautiful Mind.

In the first part of this study, coauthors Chris Martin and Tetsuro Matsuzawa compared the game play of six common chimpanzees (Pan troglodytes) and 16 Japanese students, always facing off against their own species, in the Kyoto research facility. The humans behaved as expected based on previous experiments; that is, they played reasonably well, slowly learning to predict opponent choices, but they did not play optimally. They ended up somewhat off the Nash equilibrium.

The performance of the chimps was far more impressive: they learned the game rapidly and nearly attained the predictions of the Nash theorem for optimal play. They continued to do so even as researchers introduced changes into the game, first by having players switch roles—matchers (seekers) becoming mismatchers (hiders), and vice versa—and then by adjusting the payoffs such that matchers received greater rewards when matching on one side of the screen (left or right) rather than the other. This latter adjustment changes the Nash equilibrium for the game, and the chimps changed right along with it.

In a second phase of the experiment in Bossou, Guinea, 12 adult men were asked to face one another in pairs. Instead of touching dots on a computer screen on the left or right, the men in Bossou each had a bottle cap that they placed top up or top down. As in the Kyoto experiments, one player in each pair was a mismatcher (hider) and the other was a matcher (seeker). However, the stakes were much higher in Bossou, amounting to about one full day's earnings for the winner, as opposed to the rewards for the Japanese students, who received a handful of one yen coins. Still, the players in Bossou did not match chimpanzee performance, landing as far off the Nash equilibrium as the Japanese students did.

A couple of simple explanations could account for the ability of these chimpanzees to outperform humans in the game. First, these particular chimps had more extensive training at this kind of task as well as more experience with the equipment used at the Research Institute than the human subjects did. Second, the chimps in Kyoto were related to one another—they played in mother-child pairs—and thus may have had intimate knowledge, borne of long acquaintance, of the sequence of choices their opponents would probably make.

Neither explanation seems likely, researchers say. Although the Japanese students may not have had experience with the type of touch screens employed in the Kyoto facility, they certainly had encountered video games and touch screens prior to the experiment. Meanwhile, the players in Bossou knew each other very well prior to the experiments and had the additional advantage of seeing one another while they played, yet they performed no better than the Japanese students.

Superior chimpanzee performance could be due to excellent short-term memory, a particular strength in chimps. This has been shown in other experiments undertaken at the Kyoto facility. In one game, a sequence of numbers is briefly flashed on the computer touch screen, and then the numbers quickly revert to white squares. Players must tap the squares in the sequence corresponding to the numbers they were initially shown. Chimpanzees are brilliant at this task, as video from the experiment shows; humans find it much more challenging, as seen in video from the Primate Research Center.

But before we join a species-specific pity party over our inferior brains, rest assured that researchers offer other explanations for chimpanzee superiority at the Inspection Game. There are two possible explanations that researchers currently find plausible. The first has to do with the roles of competition and cooperation in chimpanzee versus human societies; the second with the differential evolution of human and chimpanzee brains since our evolutionary paths split between 4 and 5 million years ago.

The past half-century has seen an enormous divergence of opinion as to how cooperative or competitive humans "naturally" are, and though this debate is far from settled, it is clear that wherever humans sit on the cooperative/competitive scale, common chimpanzees are more competitive with one another than we are. They create and continuously update a strong status and dominance hierarchy. (Another type of chimpanzee, Pan paniscus, or the bonobo, is considerably more cooperative than Pan troglodytes, but the former has not been studied as extensively as the latter.) Humans, in contrast, are highly prosocial and cooperative. Camerer notes that this difference is apparent in chimp and human social development. "While young chimpanzees hone their competitive skills with constant practice, playing hide-and-seek and wrestling, " says Camerer, "their human counterparts shift at a young age from competition to cooperation using our special skill at language."

Language is probably a key factor here. In the Inspection Game experiments, humans were not allowed to speak with one another, despite language being "key to human strategic interaction," according to Martin.

Language is also implicated in the "cognitive tradeoff hypothesis," the second explanation for the chimps' superior performance in the Inspection Game. According to this hypothesis, developed by Matsuzawa, the brain growth and specialization that led to distinctly human cognitive capacities such as language and categorization also caused us to process certain simpler competitive situations—like the Inspection Game—more abstractly and less automatically than our chimpanzee cousins.

These explanations remain speculative, but eventually, Bhui predicts, new technologies will make it possible to "map out the set of brain circuits that humans and chimps rely upon so we can discover whether or not human strategic choices go down a longer pathway or get diffused into different parts of the brain compared to chimps."

Funding for this experiment, described in a paper entitled "Chimpanzee choice rates in competitive games match equilibrium predictions," was provided by the Ministry of Education, Culture, Sports, Science and Technology in Japan; the Gordon and Betty Moore Foundation; the Social Sciences and Humanities Research Council of Canada; and Caltech's Division of the Humanities and Social Sciences.

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Cynthia Eller
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JCAP Stabilizes Common Semiconductors For Solar Fuels Generation

Caltech researchers devise a method to protect the materials in a solar-fuel generator

Researchers around the world are trying to develop solar-driven generators that can split water, yielding hydrogen gas that could be used as clean fuel. Such a device requires efficient light-absorbing materials that attract and hold sunlight to drive the chemical reactions involved in water splitting. Semiconductors like silicon and gallium arsenide are excellent light absorbers—as is clear from their widespread use in solar panels. However, these materials rust when submerged in the type of water solutions found in such systems.

Now Caltech researchers at the Joint Center for Artificial Photosynthesis (JCAP) have devised a method for protecting these common semiconductors from corrosion even as the materials continue to absorb light efficiently. The finding paves the way for the use of these materials in solar-fuel generators.

"For the better part of a half century, these materials have been considered off the table for this kind of use," says Nate Lewis, the George L. Argyros Professor and professor of chemistry at Caltech, and the principal investigator on the paper. "But we didn't give up on developing schemes by which we could protect them, and now these technologically important semiconductors are back on the table."

The research, led by Shu Hu, a postdoctoral scholar in chemistry at Caltech, appears in the May 30 issue of the journal Science.

In the type of integrated solar-fuel generator that JCAP is striving to produce, two half-reactions must take place—one involving the oxidation of water to produce oxygen gas; the other involving the reduction of water, yielding hydrogen gas. Each half-reaction requires both a light-absorbing material to serve as the photoelectrode and a catalyst to drive the chemistry. In addition, the two reactions must be physically separated by a barrier to avoid producing an explosive mixture of their products.

Historically, it has been particularly difficult to come up with a light-absorbing material that will robustly carry out the oxidation half-reaction. Researchers have tried, without much success, a variety of materials and numerous techniques for coating the common light-absorbing semiconductors. The problem has been that if the protective layer is too thin, the aqueous solution penetrates through and corrodes the semiconductor. If, on the other hand, the layer is too thick, it prevents corrosion but also blocks the semiconductor from absorbing light and keeps electrons from passing through to reach the catalyst that drives the reaction.

At Caltech, the researchers used a process called atomic layer deposition to form a layer of titanium dioxide (TiO2)—a material found in white paint and many toothpastes and sunscreens—on single crystals of silicon, gallium arsenide, or gallium phosphide. The key was that they used a form of TiO2 known as "leaky TiO2"—because it leaks electricity. First made in the 1990s as a material that might be useful for building computer chips, leaky oxides were rejected as undesirable because of their charge-leaking behavior. However, leaky TiO2 seems to be just what was needed for this solar-fuel generator application. Deposited as a film, ranging in thickness between 4 and 143 nanometers, the TiO2 remained optically transparent on the semiconductor crystals—allowing them to absorb light—and protected them from corrosion but allowed electrons to pass through with minimal resistance.

On top of the TiO2, the researchers deposited 100-nanometer-thick "islands" of an abundant, inexpensive nickel oxide material that successfully catalyzed the oxidation of water to form molecular oxygen.

The work appears to now make a slew of choices available as possible light-absorbing materials for the oxidation side of the water-splitting equation. However, the researchers emphasize, it is not yet known whether the protective coating would work as well if applied using an inexpensive, less-controlled application technique, such as painting or spraying the TiO2 onto a semiconductor. Also, thus far, the Caltech team has only tested the coated semiconductors for a few hundred hours of continuous illumination.

"This is already a record in terms of both efficiency and stability for this field, but we don't yet know whether the system fails over the long term and are trying to ensure that we make something that will last for years over large areas, as opposed to weeks," says Lewis. "That's the next step."

The work, titled "Amorphous TiO2 Coatings Stabilize Si, GaAs, and GaP Photoanodes for Efficient Water Oxidation," was supported by the Office of Science of the U.S. Department of Energy through an award to JCAP, a DOE Energy Innovation Hub. Some of the work was also supported by the Resnick Sustainability Institute and the Beckman Institute at Caltech. Additional coauthors on the paper are graduate students Matthew Shaner, Joseph Beardslee, and Michael Lichterman, as well as Bruce S. Brunschwig, director of the Molecular Materials Resource Center at Caltech.

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Kimm Fesenmaier
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Stabilizing Semiconductors for Solar Fuels Generation
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Miniature Truss Work

Fancy Erector Set? Nope. The elaborate fractal structure shown at right (with a close-up below) is many, many times smaller than that and is certainly not child's play. It is the latest example of what Julia Greer, professor of materials science and mechanics, calls a fractal nanotruss—nano because the structures are made up of members that are as thin as five nanometers (five billionths of a meter); truss because they are carefully architected structures that might one day be used in structural engineering materials.

Greer's group has developed a three-step process for building such complex structures very precisely. They first use a direct laser writing method called two-photon lithography to "write" a three-dimensional pattern in a polymer, allowing a laser beam to crosslink and harden the polymer wherever it is focused. At the end of the patterning step, the parts of the polymer that were exposed to the laser remain intact while the rest is dissolved away, revealing a three-dimensional scaffold. Next, the scientists coat the polymer scaffold with a continuous, very thin layer of a material—it can be a ceramic, metal, metallic glass, semiconductor, "just about anything," Greer says. In this case, they used alumina, or aluminum oxide, which is a brittle ceramic, to coat the scaffold. In the final step they etch out the polymer from within the structure, leaving a hollow architecture.

Taking advantage of some of the size effects that many materials display at the nanoscale, these nanotrusses can have unusual, desirable qualities. For example, intrinsically brittle materials, like ceramics, including the alumina shown, can be made deformable so that they can be crushed and still rebound to their original state without global failure.

"Having full control over the architecture gives us the ability to tune material properties to what was previously unattainable with conventional monolithic materials or with foams," says Greer. "For example, we can decouple strength from density and make materials that are both strong (and tough) as well as extremely lightweight. These structures can contain nearly 99 percent air yet can also be as strong as steel. Designing them into fractals allows us to incorporate hierarchical design into material architecture, which promises to have further beneficial properties."

The members of Greer's group who helped develop the new fabrication process and created these nanotrusses are graduate students Lucas Meza and Lauren Montemayor and Nigel Clarke, an undergraduate intern from the University of Waterloo.

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Kimm Fesenmaier
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Supernova Caught in the Act by Palomar Transient Factory

Supernovae—stellar explosions—are incredibly energetic, dynamic events. It is easy to imagine that they are uncommon, but the universe is a big place and supernovae are actually fairly routine. The problem with observing supernovae is knowing just when and where one is occurring and being able to point a world-class telescope at it in the hours immediately afterward, when precious data about the supernova's progenitor star is available. Fortunately the intermediate Palomar Transient Factory (iPTF) operated by Caltech scans the sky constantly in search of dramatic astrophysical events. In 2013, it caught a star in the act of exploding.

The iPTF is a robotic observing system mounted on the 48-inch Samuel Oschin Telescope on Palomar Mountain. It has been scanning the sky since February 2013. The iPTF (and its predecessor experiment, the Palomar Transient Factory [PTF], which operated between 2009 and 2012) regularly observes a wide swath of the night sky looking for astronomical objects that are moving and developing quickly, such as comets, asteroids, gamma-ray bursts, and supernovae. Both the earlier PTF and the current iPTF collaborations are led by Shrinivas Kulkarni, the John D. and Catherine T. MacArthur Professor of Astronomy and Planetary Science and director of the Caltech Optical Observatories.

Last year the iPTF discovered an object of special interest: a supernova with a spectral signature suggesting that its progenitor star was a Wolf-Rayet star. Massive stars are typically structured like an onion, with the heaviest elements in the core, while lighter elements are layered over them and then frosted, if you will, by a layer of hydrogen gas on the stellar surface. Wolf-Rayet stars, which are unusually large and hot, are exceptions to this rule, being relatively deficient in hydrogen and characterized by strong stellar winds. Astronomers have long wondered if Wolf-Rayet stars are the progenitors of certain types of supernovae, and according to a recent paper published in Nature this is just what the iPTF found in May 2013.

This supernova, SN2013cu, was picked up on a routine sky scan by the iPTF. The on-duty iPTF team member in Israel promptly sounded an alert, asking colleagues at the W. M. Keck Observatory on Mauna Kea to take a spectral image of the supernova before the sun rose in Hawaii.

When supernovae explode, they briefly ionize the sky immediately around them. The ionized materials rapidly recombine, producing unique spectral features that enable astronomers to get a full picture of the ambient material of a supernova event. This process lasts from minutes to a few days and hence is called a "flash spectrum" of the event. Flash spectrography is a novel observational method developed by Avishay Gal-Yam of the Weizmann Institute of Science in Israel, leader of the team that published the Nature paper.

In the case of SN2013cu, the flash spectrum showed relatively less hydrogen and relatively more nitrogen, suggesting that perhaps the progenitor of the supernova was a nitrogen-rich Wolf-Rayet star. This finding will enable astronomers to better understand the evolution of massive stars and identify potential progenitors of supernovae.

"I could not believe my eyes when I saw those high-ionization features perfectly matching emission lines from a Wolf-Rayet star," says Yi Cao, a graduate student from Caltech who works with Kulkarni. "Our software pipeline efforts were paying off. Now we are working even harder so that we can get flash spectra of many more supernova flavors to probe their progenitor stars."

Above all, the observation of SN2013cu highlights the success of the intermediate Palomar Transient Factory at catching the universe in the act of doing something interesting, something that might merit a second look. Though especially intriguing, SN2013cu is only one of over 2,000 supernovae that PTF/iPTF has detected during its four and a half years of observations. As Kulkarni remarks, "I am proud of how the global iPTF network is working together to invent new techniques enabling entirely new science."

The iPTF is a collaboration between Caltech, Los Alamos National Laboratory, the University of Wisconsin–Milwaukee, the Oskar Klein Centre, the Weizmann Institute of Science, the TANGO Program of the University System of Taiwan, and the Kavli Institute for the Physics and Mathematics of the Universe.

Coauthors on the paper, "A Wolf-Rayet-like progenitor of supernova SN 2013cu from spectral observations of a wind," include Kulkarni, Cao, Mansi Kasliwal, Daniel Perley, and Assaf Horesh of Caltech; Gal-Yam, I. Arcavi, E. O. Ofek, S. Ben-Ami, A. De Cia, D. Tal, P. M. Vreeswijk, and O. Yaron of the Weizmann Institute of Science; S. B. Cenko of NASA's Goddard Space Flight Center; J. C. Wheeler and J. M. Silverman of the University of Texas at Austin; F. Taddia and J. Sollerman of Stockholm University; P. E. Nugent of the Lawrence Berkeley National Laboratory; and A. V. Filippenko of UC Berkeley.

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Cynthia Eller
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Tricking the Uncertainty Principle

Caltech researchers have found a way to make measurements that go beyond the limits imposed by quantum physics.

Today, we are capable of measuring the position of an object with unprecedented accuracy, but quantum physics and the Heisenberg uncertainty principle place fundamental limits on our ability to measure. Noise that arises as a result of the quantum nature of the fields used to make those measurements imposes what is called the "standard quantum limit." This same limit influences both the ultrasensitive measurements in nanoscale devices and the kilometer-scale gravitational wave detector at LIGO. Because of this troublesome background noise, we can never know an object's exact location, but a recent study provides a solution for rerouting some of that noise away from the measurement.

The findings were published online in the May 15 issue of Science Express.

"If you want to know where something is, you have to scatter something off of it," explains Professor of Applied Physics Keith Schwab, who led the study. "For example, if you shine light at an object, the photons that scatter off provide information about the object. But the photons don't all hit and scatter at the same time, and the random pattern of scattering creates quantum fluctuations"—that is, noise. "If you shine more light, you have increased sensitivity, but you also have more noise. Here we were looking for a way to beat the uncertainty principle—to increase sensitivity but not noise."

Schwab and his colleagues began by developing a way to actually detect the noise produced during the scattering of microwaves—electromagnetic radiation that has a wavelength longer than that of visible light. To do this, they delivered microwaves of a specific frequency to a superconducting electronic circuit, or resonator, that vibrates at 5 gigahertz—or 5 billion times per second. The electronic circuit was then coupled to a mechanical device formed of two metal plates that vibrate at around 4 megahertz—or 4 million times per second. The researchers observed that the quantum noise of the microwave field, due to the impact of individual photons, made the mechanical device shake randomly with an amplitude of 10-15 meters, about the diameter of a proton.

"Our mechanical device is a tiny square of aluminum—only 40 microns long, or about the diameter of a hair. We think of quantum mechanics as a good description for the behaviors of atoms and electrons and protons and all of that, but normally you don't think of these sorts of quantum effects manifesting themselves on somewhat macroscopic objects," Schwab says. "This is a physical manifestation of the uncertainty principle, seen in single photons impacting a somewhat macroscopic thing."

Once the researchers had a reliable mechanism for detecting the forces generated by the quantum fluctuations of microwaves on a macroscopic object, they could modify their electronic resonator, mechanical device, and mathematical approach to exclude the noise of the position and motion of the vibrating metal plates from their measurement.

The experiment shows that a) the noise is present and can be picked up by a detector, and b) it can be pushed to someplace that won't affect the measurement. "It's a way of tricking the uncertainty principle so that you can dial up the sensitivity of a detector without increasing the noise," Schwab says.

Although this experiment is mostly a fundamental exploration of the quantum nature of microwaves in mechanical devices, Schwab says that this line of research could one day lead to the observation of quantum mechanical effects in much larger mechanical structures. And that, he notes, could allow the demonstration of strange quantum mechanical properties like superposition and entanglement in large objects—for example, allowing a macroscopic object to exist in two places at once.

"Subatomic particles act in quantum ways—they have a wave-like nature—and so can atoms, and so can whole molecules since they're collections of atoms," Schwab says. "So the question then is: Can you make bigger and bigger objects behave in these weird wave-like ways? Why not? Right now we're just trying to figure out where the boundary of quantum physics is, but you never know."

This work was published in an article titled "Mechanically Detecting and Avoiding the Quantum Fluctuations of a Microwave Field." Other Caltech coauthors include senior researcher Junho Suh; graduate students Aaron J. Weinstein, Chan U. Lei, and Emma E. Wollman; and Steven K. Steinke, visitor in applied physics and materials science. The work was funded by the Institute for Quantum Information and Matter, the Defense Advanced Research Projects Agency, and the National Science Foundation. The device was fabricated in Caltech's Kavli Nanoscience Institute, of which Schwab is a codirector.

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Research Update: An Autism Connection

Caltech neuroscientists find link between agenesis of the corpus callosum and autism

Building on their prior work (see "Bridging the Gap"), a team of neuroscientists at Caltech now report that rare patients who are missing connections between the left and right sides of their brain—a condition known as agenesis of the corpus callosum (AgCC)—show a strikingly high incidence of autism. The study is the first to show a link between the two disorders.

The findings are reported in a paper published April 22, 2014, in the journal Brain.

The corpus callosum is the largest connection in the human brain, connecting the left and right brain hemispheres via about 200 million fibers. In very rare cases it is surgically cut to treat epilepsy—causing the famous "split-brain" syndrome, for whose discovery the late Caltech professor Roger Sperry received the Nobel Prize. People with AgCC are like split-brain patients in that they are missing their corpus callosum—except they are born this way. In spite of this significant brain malformation, many of these individuals are relatively high-functioning individuals, with jobs and families, but they tend to have difficulty interacting with other people, among other symptoms such as memory deficits and developmental delays. These difficulties in social behavior bear a strong resemblance to those faced by high-functioning people with autism spectrum disorder.

"We and others had noted this resemblance between AgCC and autism before," explains Lynn Paul, lead author of the study and a lecturer in psychology at Caltech. But no one had directly compared the two groups of patients. This was a challenge that the Caltech team was uniquely positioned to do, she says, since it had studied patients from both groups over the years and had tested them on the same tasks.

"When we made detailed comparisons, we found that about a third of people with AgCC would meet diagnostic criteria for an autism spectrum disorder in terms of their current symptoms," says Paul, who was the founding president of the National Organization for Disorders of the Corpus Callosum.

The research was done in the laboratory of Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and a coauthor of the study. The team looked at a range of different tasks performed by both sets of patients. Some of the exercises that involved certain social behaviors were videotaped and analyzed by the researchers to assess for autism. The team also gave the individuals questionnaires to fill out that measured factors like intelligence and social functioning.

"Comparing different clinical groups on exactly the same tasks within the same lab is very rare, and it took us about a decade to accrue all of the data," Adolphs notes.

One important difference between the two sets of patients did emerge in the comparison. People with autism spectrum disorder showed autism-like behaviors in infancy and early childhood, but the same type of behaviors did not seem to emerge in individuals with AgCC until later in childhood or the teen years.

"Around ages 9 through 12, a normally formed corpus callosum goes through a developmental 'growth spurt' which contributes to rapid advances in social skills and abstract thinking during those years," notes Paul. "Because they don't have a corpus callosum, teens with AgCC become more socially awkward at the age when social skills are most important."

According to Adolphs, it is important to note that AgCC can now be diagnosed before a baby is born, using high-resolution ultrasound imaging during pregnancy. This latest development also opens the door for some exciting future directions in research.

"If we can identify people with AgCC already before birth, we should be in a much better position to provide interventions like social skills training before problems arise," Paul points out. "And of course from a research perspective it would be tremendously valuable to begin studying such individuals early in life, since we still know so little both about autism and about AgCC."

For example, the team would like to discern at what age subtle difficulties first appear in AgCC individuals, and at what point they start looking similar to autism, as well as what happens in the brain during these changes.

"If we could follow a baby with AgCC as it grows up, and visualize its brain with MRI each year, we would gain such a wealth of knowledge," Adolphs says.

The Brain paper, "Agenesis of the Corpus Callosum and Autism: A Comprehensive Comparison," also includes as coauthors Daniel Kennedy, assistant professor of psychology at Indiana University, and Christina Corsello, a member of the research staff at Rady Children's HospitalSan Diego. The research was funded by the Simons Foundation, Autism Speaks, and the Brain and Behavior Research Foundation.

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An Autism Connection
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Unlocking a Mystery of Human Disease . . . in Space

An experiment just launched into orbit by a team of Caltech researchers could be an important step toward understanding a devastating neurodegenerative disease.

Huntington's disease is a grim diagnosis. A hereditary disorder with debilitating physical and cognitive symptoms, the disease usually robs adult patients of their ability to walk, balance, and speak. More than 15 years ago, researchers revealed the disorder's likely cause—an abnormal version of the protein huntingtin; however, the mutant protein's mechanism is poorly understood, and the disease remains untreatable.

Now, a new project led by Pamela Bjorkman, Max Delbrück Professor of Biology, will investigate whether the huntingtin protein can form crystals in microgravity aboard the International Space Station (ISS)—crystals that are crucial for understanding the molecular structure of the protein. The experiment was launched from Cape Canaveral in Florida on Friday, April 18 aboard the SpaceX CRS-3 cargo resupply mission to the ISS. On Sunday, April 20 the station's robotic arm captured the mission's payload, which included the proteins for Bjorkman's experiment—which is the first Caltech experiment to take place aboard the ISS.

In the experiment, the researchers hope to grow a crystal of the huntingtin protein—the crystal would be an organized, latticelike arrangement of the protein's molecules—which is needed to determine the molecular structure of the protein. However, molecules of the huntingtin protein tend to aggregate, or clump together, in Earth's gravity. And this disordered arrangement makes it incredibly hard to parse the protein's structure, says Gwen Owens, a graduate student in Bjorkman's lab and a researcher who helped design the study.

"We need crystals for X-ray crystallography, the technique we use to study the protein, in which we shoot an X-ray through the protein crystal and analyze the organized pattern of radiation that scatters off of it," Owens says. "That pattern is what we depend on to identify the location of every carbon, nitrogen, and sulfur atom within the protein; if we shoot an X-ray beam at a clumped, aggregate protein—like huntingtin often is—we can't get any data from it," she says.

Researchers have previously studied small fragments of crystallized huntingtin, but because of its large size and propensity to clumping, no one has ever successfully grown a crystal of the full-length protein large enough to analyze with X-ray crystallography. To understand what the protein does—and how defects in it lead to the symptoms of Huntington's disease—the researchers need to study the full-length protein.

Looking for a solution to this problem, Owens was inspired by a few previous studies of protein formation on space shuttles and the ISS—studies suggesting that proteins can form crystals more readily in a condition of near-weightlessness called microgravity. "The previous studies looked at much simpler proteins, but we thought we could make a pretty good case that huntingtin would be an excellent candidate to study on the ISS," Owens says.

They proposed such an experiment to the Center for the Advancement of Science in Space (CASIS), which manages U.S. research on the ISS, and it was accepted, becoming part of the first Advancing Research Knowledge, or ARK1, mission.

Because Owens and Bjorkman cannot travel with their proteins, and staff and resources are limited aboard the ISS, the crystal will be grown with a Handheld High-Density Protein Crystal Growth device—an apparatus that will allow astronauts to initiate growth of normal and mutant huntingtin protein crystals from a solution of protein molecules with just the flip of a switch.

As the crystals grow larger over a period of several months, samples will come back to Earth via the SpaceX CRS-4 return mission. The results of the experiment are scheduled to drop into the ocean just off the coast of Southern California—along with the rest of the return cargo—sometime this fall. At that point, Owens will finally be able to analyze the proteins.

"Our ideal result would be to have large crystals of the normal and mutant huntingtin proteins right away—on the first try," she says. After analyzing crystals of the full-length protein with X-ray crystallography, the researchers could finally determine huntingtin's structure—information that will be crucial to developing treatments for Huntington's disease.

Owens, a joint MD/PhD student at Caltech and UCLA's David Geffen School of Medicine, has also had the opportunity to work with Huntington's disease patients in the clinic, adding a human connection to her experiment in the sky. "The patients and families I have met who are affected by Huntington's disease are excited to see something big like this. It's inspiring for them—and hopefully it will inspire new research, too."

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Hyperbolic Homogeneous Polynomials, Oh My!

Cutting-edge mathematics today, at least to the uninitiated, often sounds as if it bears no relation to the arithmetic we all learned in grade school. What do topology and combinatorics and n-dimensional space have to do with addition, subtraction, multiplication, and division? Yet there remains within mathematics one vibrant field of study that makes constant reference to basic arithmetic: number theory. Number theory—the "queen of mathematics," according to the famous 19th century mathematician Carl Friedrich Gauss—takes integers as its starting point. Begin counting 1, 2, 3, and you enter the domain of number theory.

Number theorists are particularly interested in prime numbers (those integers that cannot be divided by any number other than itself and 1) and Diophantine equations. Diophantine equations are polynomial equations (those with two or more variables) in which the coefficients are all integers.

It is these equations that are the inspiration for a recent proof offered by Dinakar Ramakrishnan, Caltech's Taussky-Todd-Lonergan Professor of Mathematics and executive officer for mathematics, and his coauthor, Mladen Dimitrov, formerly an Olga Taussky and John Todd Instructor in Mathematics at Caltech and now professor of mathematics at the University of Lille in France. This proof involves homogeneous equations: equations in which all the terms have the same degree. For example, the polynomial xy + z2 has degree 2, and x2yz + xy3 has degree 4.  If we take an equation like xy = z2, one solution for (x, y, z) would be (1, 4, 2). Multiplying that solution by any rational number will give infinitely many rational solutions, but this is a trivial way to get solutions achieved simply by "scaling." These are not the type of answers Ramakrishnan and Dimitrov were searching for.

What Ramakrishnan and Dimitrov showed is that a specific collection of systems of homogeneous equations with six variables has only a finite number of rational solutions (up to scaling). Usually people look for integer solutions of Diophantine equations, but the first approach is to find solutions in rational numbers—those that can be expressed as a fraction of two integers.

Diophantus, after whom the Diophantine equations are named, is best known for his Arithmetica, which Ramakrishnan describes as "a collection of intriguing mathematical problems, some of them original to Diophantus, others an assemblage of earlier work, some of it possibly going back to the Babylonians." Diophantus lived in the city of Alexandria, in what is now Egypt, during the third century CE. What makes the Arithmetica unusual is that it continues to serve as the basis for some very interesting mathematics more than 1,700 years later.

Diophantus was interested primarily in positive integers. He was aware of the existence of rational numbers, since he knew integers could divide one another, but he seemed to regard negative numbers (which are also rational numbers and can be integers) as absurd and unreal. Present-day number theorists have no such discomfort with negative numbers, but they continue to be as fascinated by integers as Diophantus was. "Integers are very special," says Ramakrishnan. "They are kind of like musical notes on a clavier. If you change a note even slightly, you'll hear a dissonance. In a sense, integers can be thought of as the well-tempered states of mathematics. They are quite beautiful."

Diophantus was especially interested in integer solutions for homogeneous polynomial equations: those in which each term of the equation has the same degree (for example, x7 + y7 = z7 or x2y3z = w6). The classic example of a homogeneous polynomial equation is the Pythagorean theorem—x2 + y2 = z2—which defines the hypotenuse, z, the longest side of a right triangle, with respect to the perpendicular sides x and y. As early as 1600 BCE, the ancient Babylonians knew that there were many integer solutions to this equation (beginning with 32 + 42 = 52), though it was Pythagoras, a Greek mathematician living in the sixth century BCE, who gave his name to the formula, and Euclid who two centuries later proved that this equation has an infinite number of positive integer solutions, known as "Pythagorean triples" (such as 3, 4, 5; 5, 12, 13; or 39, 80, 89).

In 1637, French mathematician Pierre de Fermat famously wrote in the margin of Diophantus's Arithmetica that he had a "truly marvelous proof" showing that although there were an infinite number of positive integer solutions for x2 + y2 = z2, there were no positive integer solutions at all when the variables were raised to the power of three or higher (x3 + y3 = z3; x4 + y4 = z4 ; . . . ; xn + yn = zn). Fermat did not provide the actual proof; he claimed that the margin of Diophantus's book was too small to contain it. Fermat's conjecture (it was not yet a proof, though Fermat apparently believed he had one in his mind) remained unsolved until the early 1990s, when British mathematician Andrew Wiles created a complicated and unexpected proof that made use of previously unrelated mathematical principles.

In geometric terms, Fermat's conjecture and Wiles's proof, with their three variables, operate in three-dimensional space and can be described as points on a curve on the projective plane, drawn with x, y, z coordinates up to scaling. By moving to a greater number of variables, Ramakrishnan and Dimitrov are interested in identifying points on so-called hyperbolic surfaces. A hyperbolic surface is a negatively curved space, like a saddle—as opposed to a positively curved space like a sphere—in which the rules of Euclidean geometry no longer apply. A simple example of a hyperbolic surface is given by the simultaneous solution (where the values of the variables are held constant) of three equations: x15 + y5 = z5; x25 + w5 = z5; and x35 + w5 = y5. In the 1980s, German mathematician Gerd Faltings did pioneering work on the mathematics of hyperbolic curves, work that inspired Ramakrishnan and Dimitrov.

Ramakrishnan and Dimitrov's recent finding considers rational-number solutions for several systems of homogeneous polynomial equations describing hyperbolic surfaces. One solution is to set all the variables to zero. This solution is considered trivial; but are there any nontrivial solutions?

There are at least a few nontrivial solutions that Ramakrishnan and Dimitrov use as examples. Their challenge was to determine if there are finitely many or infinitely many rational solutions. They demonstrated—in a proof-by-contradiction that took nearly two years to complete—that the hyperbolic case they consider has only a finite number of solutions.

But, as Ramakrishnan remarks, there is no rest for number theorists, because "even if we solve another bunch of equations, there are still many more that are unsolved, enough for our descendants five hundred years from now."

For Ramakrishnan, this is not a counsel of despair. He continues to find mathematics exciting, especially the concept of the mathematical proof. As he points out, "In other ancient civilizations in the Middle East or India or China, they did some very complicated math, but it was more algorithmic, more related to computer science in my opinion than to philosophy. Whereas the Greeks emphasized proofs, rigorously establishing mathematical truths. There's nothing vague about it."

Apart from the inherent joy of pushing number theory forward through another generation, Ramakrishnan points out that this field has interesting applications in both science and everyday life. "Quite often in science, you are counting. Think of balancing chemical equations such as wCH4 + xO2 —> yCO2 + zH2O, in which methane oxidizes to produce carbon dioxide and water. This is a linear Diophantine equation."

Number theory also plays an important role in encryption. "Every time one visits a website with an https:// address," says Ramakrishnan, "it is likely that the website browser is using an encryption system that validates the certificate for the remote server to which one is trying to connect. The security keys that are exchanged point to a number-theoretic solution. Most people prefer equations with simple solutions, but in some situations, such as encryption, you actually want integer equations that are hard to solve without the key. This is where number theory comes in."

Ramakrishnan and Dimitrov's paper, "Compact arithmetic quotients of the complex 2-ball and a conjecture of Lang," is posted on the math arXiv, a Cornell University Library open e-print archive for papers in physics, mathematics, computer science, quantitative biology, and quantitative finance and statistics.

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