Studying Memory's 'Ripples'

Caltech neuroscientists have looked inside brain cells as they undergo the intense bursts of neural activity known as "ripples" that are thought to underlie memory formation. 

During ripples, a small fraction of brain cells, or neurons, fire synchronously in area CA1, a part of the hippocampus that is thought to be an important relay station for memories. "During a ripple, about 10 percent of the neurons in CA1 are activated, and these active neurons all fire within a tenth of a second," says Caltech graduate student Brad Hulse. "Two big questions have been: How do the remaining 90 percent of CA1 neurons stay quiet? And what is synchronizing the firing of the active neurons?"

In a new study, published online on February 17 in the journal Neuron, Hulse and his colleagues used a novel approach to show how the combination of excitatory and inhibitory inputs to CA1 work together to synchronize the firing of active neurons while keeping most neurons silent during ripples.

"For a long time, people studied these events by placing an electrode outside of a cluster of neurons. These extracellular recordings can tell you about the output of a group of brain cells, but they tell you very little about the inputs they're receiving," says study coauthor and Caltech research scientist Evgueniy Lubenov.

The Caltech scientists combined extracellular recording with a technique to look inside a neuron during ripples. They used fine glass pipettes with tips thinner than a tenth of the width of a human hair to measure directly the voltage difference, or "electrical potential," across the cellular membrane of individual neurons in awake mice.

Employing these two techniques in tandem allowed the scientists to monitor the activity inside a single neuron while still observing how the larger network was behaving. This in turn enabled them to piece together how excitatory inputs from CA3, a hippocampal region where memories are formed, affect the output of brain cells called pyramidal neurons in CA1. These neurons are important for transferring newly coded memories to other brain areas such as the neocortex for safekeeping and long-term storage. Ripples are thought to be the mechanism by which this transfer occurs.

The team discovered that the membrane potential of CA1 pyramidal cells increases during ripples. Surprisingly, this increase is relatively constant and independent of the strength of the input from CA3. For this to be the case, the direct excitation from CA3 must be balanced by proportional inhibition. The source of this inhibition is presumed to be a class of brain cells called feedforward interneurons, which receive direct inputs from CA3 and inhibit CA1 pyramidal cells.

"There seems to be a circuit mechanism that balances excitation and inhibition, so that for most neurons, these two forces cancel out," says study leader Thanos Siapas, professor of computation and neural systems at Caltech.

Without a balanced inhibition, all of the neurons in CA1 could fire when the excitatory input is large enough. "This could cause runaway excitation and possibly trigger a seizure," says Hulse, who is the first author of the new study.

The team's finding explains why most CA1 pyramidal neurons remain silent during ripples, but it raises two important questions: Why do any neurons fire at all? And what controls the precise timing of those that do fire?

The Caltech researchers found that active neurons receive a much stronger excitatory input from CA3 than silent neurons do—one that is large enough to overcome the balancing inhibition. This large excitation originates from CA3 neurons with particularly strong connections to the active CA1 neurons. These connections are believed to be modified during behavior to encode memories.

Hence, it is the specific identity of CA3 neurons, rather than their sheer number, that is responsible for making CA1 neurons fire, the researchers say. This system might seem overly complex and redundant, but the end result is a flexible circuit—an ever-changing mosaic of active and inactive pyramidal neurons. "It's a shifting mosaic, but it's one that is dependent on the organism's memories and experience," Siapas says.

How do ripples exert their influence on the rest of the brain? The membrane potential of each neuron oscillates very rapidly during ripples to synchronize the firing of cells to within a few thousandths of a second. "By coordinating their activities, the CA1 neurons are maximizing the impact of their output on downstream areas of the brain. The overall effect is more powerful than if each neuron fired independently," Lubenov says. "It is the difference between clapping independently or in unison with others at a concert. The effect in the latter case is stronger, even with the same number of people applauding."

Neuroscientists previously thought that these fast oscillations were generated by rhythmic firing of inhibitory neurons, but the Caltech team showed that this cannot be the whole story. "Our experiments suggest that it is the interplay between rhythmic excitation and inhibition that drives these fast oscillations," Hulse says.

The paper, "Membrane Potential Dynamics of CA1 Pyramidal Neurons during Hippocampal Ripples in Awake Mice," is also coauthored by Laurent C. Moreaux, a research scientist at Caltech. Funding for the work was provided by the Mathers Foundation, the Gordon and Betty Moore Foundation, the National Institutes of Health, and the National Science Foundation. 

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Neuroscientists look inside brain cells undergoing the bursts of activity, or "ripples," that underlie memory formation

Counting Molecules with an Ordinary Cell Phone

Diagnostic health care is often restricted in areas with limited resources, because the procedures required to detect many of the molecular markers that can diagnose diseases are too complex or expensive to be used outside of a central laboratory. Researchers in the lab of Rustem Ismagilov, Caltech's Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering and director of the Jacobs Institute for Molecular Engineering for Medicine, are inventing new technologies to help bring emerging diagnostic capabilities out of laboratories and to the point of care. Among the important requirements for such diagnostic devices is that the results—or readouts—be robust against a variety of environmental conditions and user errors.

To address the need for a robust readout system for quantitative diagnostics, researchers in the Ismagilov lab have invented a new visual readout method that uses analytical chemistries and image processing to provide unambiguous quantification of single nucleic-acid molecules that can be performed by any cell-phone camera.

The visual readout method is described and validated using RNA from the hepatitis C virus—HCV RNA—in a paper in the February 22 issue of the journal ACS Nano.

The work utilizes a microfluidic technology called SlipChip, which was invented in the Ismagilov lab several years ago. A SlipChip serves as a portable lab-on-a-chip and can be used to quantify concentrations of single molecules. Each SlipChip encodes a complex program for isolating single molecules (such as DNA or RNA) along with chemical reactants in nanoliter-sized wells. The program also controls the complex reactions in each well: the chip consists of two plates that move—or "slip"—relative to one another, with each "slip" joining or separating the hundreds or even thousands of tiny wells, either bringing reactants and molecules into contact or isolating them. The architecture of the chip enables the user to have complete control over these chemical reactions and can prevent contamination, making it an ideal platform for a user-friendly, robust diagnostic device.

The new visual readout method builds upon this SlipChip platform. Special indicator chemistries are integrated into the wells of the SlipChip device. After an amplification reaction—a reaction that multiplies nucleic-acid molecules—wells change color depending on whether the reaction in it was positive or negative. For example, if a SlipChip is being used to count HCV RNA molecules in a sample, a well containing an RNA molecule that amplified during the reaction would turn blue; whereas a well lacking an RNA molecule would remain purple.

To read the result, a user simply takes a picture of the entire SlipChip using any camera phone. Then the photo is processed using a ratiometric approach that transforms the colors detected by the camera's sensor into an unambiguous readout of positives and negatives.

Previous SlipChip technologies utilized a chemical that would fluoresce when a reaction took place within a well. But those readouts can be too subtle for detection by a common cell-phone camera or can require specific lighting conditions. The new method provides guidelines for selecting indicators that yield color changes compatible with the color sensitivities of phone cameras, and the ratiometric processing removes the need for a user to distinguish colors by sight.

"The readout process we developed can be used with any cell-phone camera," says Jesus Rodriguez-Manzano, a postdoctoral scholar in chemical engineering and one of two first authors on the paper. "It is rapid, automated, and doesn't require counting or visual interpretation, so the results can be read by anyone—even users who are color blind or working under poor lighting conditions. This robustness makes our visual readout method appropriate for integration with devices used in any setting, including at the point of care in limited-resource settings. This is critical because the need for highly sensitive diagnostics is greatest in such regions."

The paper is titled "Reading Out Single-Molecule Digital RNA and DNA Isothermal Amplification in Nanoliter Volumes with Unmodified Camera Phones." In addition to Rodriguez-Manzano, Mikhail Karymov is also a first author. Other Caltech coauthors include Stefano Begolo, David Selck, Dmitriy Zhukov, and Erik Jue. The work was funded by grants from the Defense Advanced Research Projects Agency, the National Institutes of Health, and an Innovation in Regulatory Science Award from the Burroughs Wellcome Fund. Microfluidic technologies developed by Ismagilov's group have been licensed to Emerald BioStructures, RainDance Technologies, and SlipChip Corp., of which Ismagilov is a founder.

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A New Twist on the History of Life

The idea that the wholesale relocation of Earth's continents 520 million years ago, also known as "true polar wander," coincided with a burst of animal speciation in the fossil record dates back almost 20 years to an original hypothesis by Joseph Kirschvink (BS, MS '75), Caltech's Nico and Marilyn Van Wingen Professor of Geobiology, and his colleagues. For more than a century, paleontologists including Charles Darwin have debated whether the so-called Cambrian explosion—a rapid period of species diversification that began around 542 million years ago—was the equivalent of an evolutionary "big bang" of biological innovation, or just an artifact of the incomplete fossil record.

In a new study published in the December issue of the American Journal of Science, a team of researchers including Kirschvink and Ross Mitchell, a postdoctoral scholar in geology at Caltech, describes a new model showing that during the proposed Cambrian true polar wander event, most continents would have moved toward the equator instead of toward the poles.

"It's long been observed that biological diversity is highest in the tropics, where nutrients and energy tend to be abundant," says Kirschvink. "One of the side effects of true polar wander is that sea level rises near the equator but falls near the poles, so the equatorial migration of most Cambrian land masses would have enhanced diversification into previously lower-diversity environments."

Using a model they developed, the team simulated the pattern of continental migration during the Cambrian and found that their results can explain the distribution of Cambrian fossils.

"Our model provides an explanation for why the fossil record looks the way it does, with many Cambrian fossil groups on some continents but few on others," says study coauthor Tim Raub (BS, MS '02), a lecturer at the University of St. Andrews in Scotland.

"The same sea-level rise which flooded those continents that shifted to the tropics and opened new ecological niches for faster speciation also led to more fossil preservation," Mitchell says. "In contrast, the few areas that shifted to the poles became less biologically diverse and also lost rock volume to erosion following sea-level drops due to true polar wander."

The scientists say their new findings could help resolve the debate started so long ago by Darwin. If their theory is correct, the Cambrian explosion is both a true and dramatic pulse of biological innovation and an expression of preferentially preserved shells on selectively submerged continental margins capable of containing fossils.

Funding for the study was provided by the National Science Foundation.

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Caltech Biologists Identify Gene That Helps Regulate Sleep

Caltech biologists have performed the first large-scale screening in a vertebrate animal for genes that regulate sleep, and have identified a gene that when overactivated causes severe insomnia. Expression of the gene, neuromedin U (Nmu), also seems to serve as nature's stimulant—fish lacking the gene take longer to wake up in the morning and are less active during the day.

The findings improve our understanding of how sleep is regulated—a process that we know surprisingly little about despite its clear importance. In the long term, the results suggest Nmu as a potential candidate for new therapies to address sleep disorders.

A paper describing the new screening process and its results appears in the February 17, 2016, issue of the journal Neuron. David Prober, assistant professor of biology at Caltech, began the work as a postdoctoral fellow at Harvard University, and has continued the work at Caltech since 2009. The lead authors on the paper are Cindy Chiu (PhD '14), a former graduate student in Prober's lab, and Jason Rihel, who collaborated with Prober at Harvard and now has his own lab at University College London.

"Sleep is a mysterious process," says Prober. "We spend a third of our lives doing it, and every animal with a complex nervous system seems to do it, so it must be important. But we still don't understand why we do it or how it's regulated."

Genetic screens are a powerful method that can help identify the genetic basis of such behaviors. They typically involve mutating the DNA of thousands of animals, raising them, identifying any resulting physical or behavioral differences, and determining which altered gene produced each mutation. This approach works well for simple model organisms, such as fruit flies and worms, because their anatomy is relatively simple and it is easy to raise large numbers of them, but is far more difficult in vertebrates, such as rodents.

Recently, zebrafish have emerged as a valuable vertebrate model system for studying sleep. Compared to a mouse, the small, striped fish are much easier to work with. Many can be raised in a small space (a larva is about 4 millimeters long, about the same size as a fruit fly); they develop quickly, exhibiting complex behaviors, such as hunting, by the time they are five days old; and they are transparent during their embryonic and larval stages, making it simpler for researchers to track what is happening inside their brains. Like humans, zebrafish sleep for consolidated periods of time at night. Furthermore, Prober says, "anatomical and molecular similarities between zebrafish and mammalian brains suggest that the basic neural circuits regulating sleep in zebrafish are likely conserved in mammals."

Rather than mutating the DNA and testing which functions were lost, the researchers used a gain-of-function approach in the new study. Just after fertilization, when the zebrafish embryos were still single cells, the researchers injected them with a DNA molecule, called a plasmid, carrying a gene that was inserted into the genome of some of the cells in each fish. In particular, they wanted to test genes that are predicted to encode for secreted proteins—those, like neuropeptides, that cells make and then release. Many of the genes that have been identified as being involved in sleep encode neuropeptides.

Using a genetic switch called a heat-shock promoter, which turns on only when the fish are heated to about 37 degrees Celsius, the biologists were able to control when the fish expressed each inserted gene. They kept the switch on long enough for the fish to overexpress each gene, making many copies of the products. Then they used computerized video trackers to monitor the fish for several days to see which genes affected sleep.

Next, the researchers made transgenic zebrafish for each of the genes that had demonstrated strong effects on sleep in the genetic screen. That labor-intensive approach gave them zebrafish in which all cells overexpressed a particular gene in response to heat shock, providing more robust results.

In the end, the most significant change resulted from overexpression of Nmu, a gene that is also found in mammals and is expressed in a part of the brain called the hypothalamus.

"After heat shock, the fish that overexpress Nmu are much more active both during the day and at night," says Prober. "The fish almost don't sleep at all the night following the heat shock—so they display a very profound form of insomnia."

When the researchers mutated the zebrafish so that they did not have Nmu, the larvae were less active during the day. Adult fish without the gene were particularly sluggish first thing in the morning.

Like humans, zebrafish normally start to wake up at the end of the night and then become much more active when the lights turn on. "The fish without Nmu are defective in this anticipation of dawn," says Prober. "So it seems that this gene is particularly important for the transition from nighttime sleep to daytime wakefulness."

To explore how Nmu promotes wakefulness, the researchers first investigated the gene's role in a stress response pathway known as the hypothalamic-pituitary-adrenal (HPA) axis. Researchers had previously shown Nmu to be involved in arousal caused by stressful situations and hypothesized that it was involved in activating the HPA axis. However, Prober and his colleagues found that Nmu suppressed sleep to the same extent in zebrafish mutants lacking a protein called the glucocorticoid receptor, which is necessary for HPA axis signaling, as it did in fish with a functional glucocorticoid receptor, suggesting that the gene does not act through the HPA axis.

The researchers then went back to the drawing board and asked which neurons in the brain became activated as a result of Nmu overexpression. Using a technique that labels activated neurons, they saw strong activation of a handful of cells that express a gene called corticotrophin-releasing hormone (CRH) in the brainstem.

"That was surprising because CRH is the gene that initiates the HPA axis response, but the cells that do that are in the hypothalamus, a different part of the brain, and they aren't activated when we overexpress Nmu," says Prober. "It's another population of CRH cells in the brainstem that are activated by Nmu overexpression."

A low dose of a drug that blocks CRH signaling completely blocked the wake-promoting effect of Nmu overexpression in zebrafish, the researchers found, whereas a higher dose also reduced wakefulness in normal fish.

"So not only is CRH signaling required for the effects of Nmu on behavior, it's also required for normal levels of activity," explains Prober.

Several wake-promoting or sleep-promoting genes and neurons have been identified, he notes. However, scientists still do not know which are the relevant ones for causing sleep disorders in humans. "Our study suggests that Nmu could be a good gene to look into."

Additional Caltech authors on the paper, "A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States," are Daniel A. Lee, Chanpreet Singh, Eric A. Mosser, Shijia Chen, Viveca Sapin, Uyen Pham, Jae Engle, Brett J. Niles, Christin J. Montz, and Sridhara Chakravarthy. Steven Zimmerman and Alexander F. Schier are additional authors from Harvard University. Kourosh Salehi-Ashtiani and Marc Vidal are authors from Harvard Medical School. The work was supported by grants from the National Institutes of Health, the European Research Council, University College London, the High-Tech Fund of the Dana Farber Cancer Institute, the Ellison Foundation, the Edward Mallinckrodt, Jr. Foundation, the Rita Allen Foundation, and the Brain and Behavior Research Foundation.

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By conducting a genetic screen in zebrafish, biologists have identified a gene that seems to serve as nature's stimulant.

Gravitational Waves Detected 100 Years After Einstein’s Prediction

LIGO opens new window on the universe with observation of gravitational waves from colliding black holes

For the first time, scientists have observed ripples in the fabric of spacetime called gravitational waves, arriving at the earth from a cataclysmic event in the distant universe. This confirms a major prediction of Albert Einstein's 1915 general theory of relativity and opens an unprecedented new window onto the cosmos.

Gravitational waves carry information about their dramatic origins and about the nature of gravity that cannot otherwise be obtained. Physicists have concluded that the detected gravitational waves were produced during the final fraction of a second of the merger of two black holes to produce a single, more massive spinning black hole. This collision of two black holes had been predicted but never observed.

The gravitational waves were detected on September 14, 2015 at 5:51 a.m. Eastern Daylight Time (09:51 UTC) by both of the twin Laser Interferometer Gravitational-wave Observatory (LIGO) detectors, located in Livingston, Louisiana, and Hanford, Washington, USA. The LIGO Observatories are funded by the National Science Foundation (NSF), and were conceived, built, and are operated by Caltech and MIT. The discovery, accepted for publication in the journal Physical Review Letters, was made by the LIGO Scientific Collaboration (which includes the GEO Collaboration and the Australian Consortium for Interferometric Gravitational Astronomy) and the Virgo Collaboration using data from the two LIGO detectors.

Based on the observed signals, LIGO scientists estimate that the black holes for this event were about 29 and 36 times the mass of the sun, and the event took place 1.3 billion years ago. About 3 times the mass of the sun was converted into gravitational waves in a fraction of a second—with a peak power output about 50 times that of the whole visible universe. By looking at the time of arrival of the signals—the detector in Livingston recorded the event 7 milliseconds before the detector in Hanford—scientists can say that the source was located in the Southern Hemisphere.

According to general relativity, a pair of black holes orbiting around each other lose energy through the emission of gravitational waves, causing them to gradually approach each other over billions of years, and then much more quickly in the final minutes. During the final fraction of a second, the two black holes collide into each other at nearly one-half the speed of light and form a single more massive black hole, converting a portion of the combined black holes' mass to energy, according to Einstein's formula E=mc2. This energy is emitted as a final strong burst of gravitational waves. It is these gravitational waves that LIGO has observed.

LIGO was originally proposed as a means of detecting these gravitational waves in the 1980s by Rainer Weiss, professor of physics, emeritus, from MIT; Kip Thorne, Caltech's Richard P. Feynman Professor of Theoretical Physics, emeritus; and Ronald Drever, professor of physics, emeritus, also from Caltech.

"With this discovery, we humans are embarking on a marvelous new quest: the quest to explore the warped side of the universe—objects and phenomena that are made from warped spacetime. Colliding black holes and gravitational waves are our first beautiful examples," says Thorne.

 "The description of this observation is beautifully described in the Einstein theory of general relativity formulated 100 years ago and comprises the first test of the theory in strong gravitation. It would have been wonderful to watch Einstein's face had we been able to tell him," says Weiss.

"Caltech thrives on posing fundamental questions and inventing new instruments to answer them," says Caltech president Thomas Rosenbaum, the Sonja and William Davidow Presidential Chair and professor of physics. "LIGO represents an exhilarating example of how this approach can transform our knowledge of the universe. We are proud to partner with NSF and MIT and our other scientific collaborators to lead this decades-long effort."

"Our observation of gravitational waves accomplishes an ambitious goal set out over five decades ago to directly detect this elusive phenomenon and better understand the universe, and, fittingly, fulfills Einstein's legacy on the 100th anniversary of his general theory of relativity," says Caltech's David H. Reitze, executive director of the LIGO Laboratory.

"This discovery is just the beginning," says Fiona Harrison, the Benjamin M. Rosen Professor of Physics and holder of the Kent and Joyce Kresa Leadership Chair of the Division of Physics, Mathematics and Astronomy. "Over the next years, LIGO will be putting general relativity to its most stringent tests ever, it will be discovering new sources of gravitational waves, and we will be using telescopes on the ground and in space to search for light emitted by these catastrophic events."

The existence of gravitational waves was first demonstrated in the 1970s and 80s by Joseph Taylor, Jr., and colleagues. Taylor and Russell Hulse discovered in 1974 a binary system composed of a pulsar in orbit around a neutron star. Taylor and Joel M. Weisberg in 1982 found that the orbit of the pulsar was slowly shrinking over time because of the release of energy in the form of gravitational waves. For discovering the pulsar and showing that it would make possible this particular gravitational wave measurement, Hulse and Taylor were awarded the Nobel Prize in Physics in 1993.

The new LIGO discovery is the first observation of gravitational waves themselves, made by measuring the tiny disturbances the waves make to space and time as they pass through the earth.

LIGO research is carried out by the LIGO Scientific Collaboration (LSC), a group of more than 1000 scientists from universities around the United States and in 14 other countries. More than 90 universities and research institutes in the LSC develop detector technology and analyze data; approximately 250 students are strong contributing members of the collaboration. The LSC detector network includes the LIGO interferometers and the GEO600 detector. The GEO team includes scientists at the Max Planck Institute for Gravitational Physics (Albert Einstein Institute, AEI), Leibniz Universität Hannover, along with partners at the University of Glasgow, Cardiff University, the University of Birmingham, other universities in the United Kingdom, and the University of the Balearic Islands in Spain.

"This detection is the beginning of a new era: The field of gravitational wave astronomy is now a reality," says Gabriela González, LSC spokesperson and professor of physics and astronomy at Louisiana State University.

The discovery was made possible by the enhanced capabilities of Advanced LIGO, a major upgrade that increases the sensitivity of the instruments compared to the first generation LIGO detectors, enabling a large increase in the volume of the universe probed—and the discovery of gravitational waves during its first observation run. The US National Science Foundation leads in financial support for Advanced LIGO. Funding organizations in Germany (Max Planck Society), the U.K. (Science and Technology Facilities Council, STFC) and Australia (Australian Research Council) also have made significant commitments to the project. Several of the key technologies that made Advanced LIGO so much more sensitive have been developed and tested by the German UK GEO collaboration. Significant computer resources have been contributed by the AEI Hannover Atlas Cluster, the LIGO Laboratory, Syracuse University, and the University of Wisconsin-Milwaukee. Several universities designed, built, and tested key components for Advanced LIGO: The Australian National University, the University of Adelaide, the University of Florida, Stanford University, Columbia University of New York, and Louisiana State University.

"In 1992, when LIGO's initial funding was approved, it represented the biggest investment the NSF had ever made," says France Córdova, NSF director. "It was a big risk. But the National Science Foundation is the agency that takes these kinds of risks. We support fundamental science and engineering at a point in the road to discovery where that path is anything but clear. We fund trailblazers. It's why the U.S. continues to be a global leader in advancing knowledge."

"The Advanced LIGO detectors are a tour de force of science and technology, made possible by a truly exceptional international team of technicians, engineers, and scientists," says David Shoemaker of MIT, the project leader for Advanced LIGO. "We are very proud that we finished this NSF-funded project on time and on budget, and delighted Advanced LIGO delivered its groundbreaking detection so quickly."

At each observatory, the two-and-a-half-mile (4-km) long L-shaped LIGO interferometer uses laser light split into two beams that travel back and forth down the arms (four-foot diameter tubes kept under a near-perfect vacuum). The beams are used to monitor the distance between mirrors precisely positioned at the ends of the arms. According to Einstein's theory, the distance between the mirrors will change by an infinitesimal amount when a gravitational wave passes by the detector. A change in the lengths of the arms smaller than one-ten-thousandth the diameter of a proton (10-19 meter) can be detected.

Independent and widely separated observatories are necessary to determine the direction of the event causing the gravitational waves, and also to verify that the signals come from space and are not from some other local phenomenon.

A network of detectors will significantly help to localize the sources. The Virgo detector will be the first to join later this year.

The LIGO Laboratory also is working closely with scientists in India at the Inter-University Centre for Astronomy and Astrophysics, the Raja Ramanna Centre for Advanced Technology, and the Institute for Plasma to establish a third Advanced LIGO detector on the Indian subcontinent. Awaiting approval by the government of India, it could be operational early in the next decade. The additional detector will greatly improve the ability of the global detector network to localize gravitational-wave sources.

Virgo research is carried out by the Virgo Collaboration, consisting of more than 250 physicists and engineers belonging to 19 different European research groups: 6 from Centre National de la Recherche Scientifique (CNRS) in France; 8 from the Istituto Nazionale di Fisica Nucleare (INFN) in Italy; 2 in The Netherlands with Nikhef; the Wigner RCP in Hungary; the POLGRAW group in Poland, and the European Gravitational Observatory (EGO), the laboratory hosting the Virgo detector near Pisa in Italy.

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Social Hormone Promotes Cooperation in Risky Situations

A hormone implicated in monogamy and aggression in animals also promotes trust and cooperation in humans in risky situations, Caltech researchers say.

The findings, published the week of February 8 in the online edition of the Proceedings of the National Academy of Sciences, could prove useful for helping groups cooperate beneficially.

Research in rodents shows the hormone arginine vasopressin (AVP) promotes monogamous pair bonding and parental behavior, but also aggression in males. "Part of the dark side of monogamy is that an AVP-pumped-up male is more likely to behave aggressively toward intruders," says study coauthor Colin Camerer, the Robert Kirby Professor of Behavioral Economics at Caltech.

In the new study, Camerer and his team tested the hypothesis that AVP might also play a role in social bonding in people and could help explain our species' cooperative tendencies. "One of the reasons humans rule the world rather than apes is that we do things that require a great deal of trust. We cooperate in large-scale groups," Camerer says. "Where does that come from? Is it something like pair bonding but just scaled up? And if it is, what role does AVP play?"

To investigate these questions, Camerer and his colleagues administered a nasal spray containing AVP or a hormone-free nasal spray (a placebo) to 59 male volunteers, aged 19 to 32 years old. Pairs of subjects then used computers to play a so-called assurance game in which they had to choose whether or not to cooperate with another player; "assurance" comes from the fact that subjects will take a risky action if they are sufficiently assured that others will, too. When they cooperated, both players received more points than they would have if they did not mutually cooperate. If one player chose not to cooperate but his partner made the opposite decision, the non-cooperative player received an intermediate payoff whereas the cooperative player received nothing.

"The game is designed to mimic situations in which people are willing to help, but only if everyone else helps too," Camerer says. "Think of pitching in on a team project, or of a group of soldiers rushing the enemy. If a critical mass cooperates, then everyone else should go along. Thus it is in your best interest to help only if enough others do."

To help ensure the players were engaged, the points they accumulated were converted into actual money at the end of the game (usually around $20).

The experiment showed that players who received AVP before the game were significantly more likely to cooperate than those who received the placebo. "By targeting a specific hormonal system in the human brain, we could manipulate people's willingness to cooperate and help them do better," says Gideon Nave, a graduate student in Camerer's lab and a coauthor on the study.

Using control experiments, the researchers were also able to rule out other explanations for why the subjects were cooperating. For example, one possibility is that AVP was increasing the subjects' appetite for risks. Alternatively, the administered hormone might be amplifying their altruistic tendencies, so that they just wanted to help other people regardless of the risk to themselves.

"We found that when we asked them, 'Do you want to just give some money to this stranger?' they don't do it," Camerer says. "So AVP seems to be quite specialized to this particular type of risky cooperation."

To better understand the neural mechanism underlying AVP's effect on risky cooperation, the researchers conducted the same experiment but this time had subjects—a separate group of 34 men—play the game while their brains were being imaged using a functional magnetic resonance imaging (fMRI) scanner. The scans indicated that after AVP administration, a part of the brain's reward system known as the ventral pallidum—a region that is known to have an abundance of AVP receptors—showed a change in neural activity when the players decided to cooperate.

"That was very encouraging, because it showed that the hormone is activating a part of the brain that is known to be rich in AVP receptors," Camerer says.

Could the discovery that AVP increases the likelihood of risky cooperation have practical applications and be used, for example, to engender trust and foster cooperation in groups? Perhaps.

"You could imagine a high-stakes situation, such as a military operation, in which people have to trust each other to all do something difficult and it fails if anyone chickens out," Camerer says. "In that case, you might want to administer AVP to help ensure that everyone is cooperative."

In addition to Camerer and Nave, other coauthors on the paper, "Vasopressin increases human risky cooperative behavior," include Claudia Brunnlieb, Stephan Schosser, and Bodo Vogt of the University of Magdeburg and Thomas Münte and Marcus Heldmann at the University of Lübeck in Germany. The research was funded by a special grant of the Center for Behavioral Brain Sciences and by the Gordon and Betty Moore Foundation. 

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A hormone implicated in monogamy and aggression in animals also promotes trust and cooperation in humans in risky situations, Caltech researchers say.

Delivering Genes Across the Blood-Brain Barrier

Caltech biologists have modified a harmless virus in such a way that it can successfully enter the adult mouse brain through the bloodstream and deliver genes to cells of the nervous system. The virus could help researchers map the intricacies of the brain and holds promise for the delivery of novel therapeutics to address diseases such as Alzheimer's and Huntington's. In addition, the screening approach the researchers developed to identify the virus could be used to make additional vectors capable of targeting cells in other organs.

"By figuring out a way to get genes across the blood-brain barrier, we are able to deliver them throughout the adult brain with high efficiency," says Ben Deverman, a senior research scientist at Caltech and lead author of a paper describing the work in the February 1 online publication of the journal Nature Biotechnology.

The blood-brain barrier allows the body to keep pathogens and potentially harmful chemicals circulating in the blood from entering the brain and spinal cord. The semi-permeable blockade, composed of tightly packed cells, is crucial for maintaining a controlled environment to allow the central nervous system to function properly. However, the barrier also makes it nearly impossible for many drugs and other molecules to be delivered to the brain via the bloodstream.

To sneak genes past the blood-brain barrier, the Caltech researchers used a new variant of a small, harmless virus called an adeno-associated virus (AAV). Over the past two decades, researchers have used various AAVs as vehicles to transport specific genes into the nuclei of cells; once there, the genes can be expressed, or translated, from DNA into proteins. In some applications, the AAVs carry functional copies of genes to replace mutated forms present in individuals with genetic diseases. In other applications, they are used to deliver genes that provide instructions for generating molecules such as antibodies or fluorescent proteins that help researchers study, identify, and track certain cells.

Largely because of the blood-brain barrier problem, scientists have had only limited success delivering AAVs and their genetic cargo to the central nervous system. In general, they have relied on surgical injections, which deliver high concentrations of the virus at the injection site but little to the outlying areas. Such injections are also quite invasive. "One has to drill a hole through skull, then pierce tissue with a needle to the injection site," explains Viviana Gradinaru (BS '05), assistant professor of biology and biological engineering at Caltech and senior author on the paper. "The deeper the injection, the higher the risk of hemorrhage. With systemic injection, using the bloodstream, none of that damage happens, and the delivery is more uniform."

In addition, Gradinaru notes, "many disorders are not tightly localized. Neurodegenerative disorders like Huntington's disease affect very large brain areas. Also, many complex behaviors are mediated by distributed interacting networks. Our ability to target those networks is key in terms of our efforts to understand what those pathways are doing and how to improve them when they are not working well."

In 2009, a group led by Brian Kaspar of Ohio State University published a paper, also in Nature Biotechnology, showing that an AAV strain called AAV9 injected into the bloodstream could make its way into the brain—but it was only efficient when used in neonatal, or infant, mice.

"The big challenge was how do we achieve the same efficiency in an adult," says Gradinaru.

Although one might like to design an AAV that is up to the task, the number of variables that dictate the behavior of any given virus, as well as the intricacies of the brain and its barrier, make that extremely challenging. Instead, the researchers developed a high-throughput selection assay, CREATE (Cre REcombinase-based AAV Targeted Evolution), that allowed them to test millions of viruses in vivo simultaneously and to identify those that were best at entering the brain and delivering genes to a specific class of brain cells known as astrocytes.

They started with the AAV9 virus and modified a gene fragment that codes for a small loop on the surface of the capsid—the protein shell of the virus that envelops all of the virus' genetic material. Using a common amplification technique, known as polymerase chain reaction (PCR), they created millions of viral variants. Each variant carried within it the genetic instructions to produce more capsids like itself.

Then they used their novel selection process to determine which variants most effectively delivered genes to astrocytes in the brain. Importantly, the new process relies on strategically positioning the gene encoding the capsid variants on the DNA strand between two short sequences of DNA, known as lox sites. These sites are recognized by an enzyme called Cre recombinase, which binds to them and inverts the genetic sequence between them. By injecting the modified viruses into transgenic mice that only express Cre recombinase in astrocytes, the researchers knew that any sequences flagged by the lox site inversion had successfully transferred their genetic cargo to the target cell type—here, astrocytes.

After one week, the researchers isolated DNA from brain and spinal cord tissue, and amplified the flagged sequences, thereby recovering only the variants that had entered astrocytes.

Next, they took those sequences and inserted them back into the modified viral genome to create a new library that could be injected into the same type of transgenic mice. After only two such rounds of injection and amplification, a handful of variants emerged as those that were best at crossing the blood-brain barrier and entering astrocytes.

"We went from millions of viruses to a handful of testable, potentially useful hits that we could go through systematically and see which ones emerged with desirable properties," says Gradinaru.

Through this selection process, the researchers identified a variant dubbed AAV-PHP.B as a top performer. They gave the virus its acronym in honor of the late Caltech biologist Paul H. Patterson because Deverman began this work in Patterson's group. "Paul had a commitment to understanding brain disorders, and he saw the value in pushing tool development," says Gradinaru, who also worked in Patterson's lab as an undergraduate student.

To test AAV-PHP.B, the researchers used it to deliver a gene that codes for a protein that glows green, making it easy to visualize which cells were expressing it. They injected the AAV-PHP.B or AAV9 (as a control) into different adult mice and after three weeks used the amount of green fluorescence to assess the efficacy with which the viruses entered the brain, the spinal cord, and the retina.

"We could see that AAV-PHP.B was expressed throughout the adult central nervous system with high efficiency in most cell types," says Gradinaru. Indeed, compared to AAV9, AAV-PHP.B delivers genes to the brain and spinal cord at least 40 times more efficiently.  

"What provides most of AAV-PHP.B's benefit is its increased ability to get through the vasculature into the brain," says Deverman. "Once there, many AAVs, including AAV9 are quite good at delivering genes to neurons and glia."

Gradinaru notes that since AAV-PHP.B is delivered through the bloodstream, it reaches other parts of the body. "Although in this study we were focused on the brain, we were also able to use whole-body tissue clearing to look at its biodistribution throughout the body," she says.

Whole-body tissue clearing by PARS CLARITY, a technique developed previously in the Gradinaru lab to make normally opaque mammalian tissues transparent, allows organs to be examined without the laborious task of making thin slide-mounted sections. Thus, tissue clearing allows researchers to more quickly screen the viral vectors for those that best target the cells and organs of interest.

"In this case, the priority was to express the gene in the brain, but we can see by using whole-body clearing that you can actually have expression in many other organs and even in the peripheral nerves," explains Gradinaru. "By making tissues transparent and looking through them, we can obtain more information about these viruses and identify targets that we might overlook otherwise."

The biologists conducted follow-up studies up to a year after the initial injections and found that the protein continued to be expressed efficiently. Such long-term expression is important for gene therapy studies in humans. 

In collaboration with colleagues from Stanford University, Deverman and Gradinaru also showed that AAV-PHP.B is better than AAV9 at delivering genes to human neurons and glia.

The researchers hope to begin testing AAV-PHP.B's ability to deliver potentially therapeutic genes in disease models. They are also working to further evolve the virus to make even better performing variants and to produce variants that target certain cell types with more specificity.

Deverman says that the CREATE system could indeed be applied to develop AAVs capable of delivering genes specifically to many different cell types. "There are hundreds of different Cre transgenic lines available," he says. "Researchers have put Cre recombinase under the control of gene regulatory elements so that it is only made in certain cell types. That means that regardless of whether your objective is to target liver cells or a particular type of neuron, you can almost always find a mouse that has Cre recombinase expressed in those cells."

"The CREATE system gave us a good hit early on, but we are excited about the future potential of using this approach to generate viruses that have very good cell-type specificity in different organisms, especially the less genetically tractable ones," says Gradinaru. "This is just the first step. We can take these tools and concepts in many exciting directions to further enhance this work, and we—with the Beckman Institute and collaborators—are ready to pursue those possibilities." 

The Beckman Institute at Caltech recently opened a resource center called CLOVER (CLARITY, Optogenetics, and Vector Engineering Research Center) to support such research efforts involving tissue clearing and imaging, optogenetic studies, and custom gene-delivery vehicle development. Deverman is the center's director, and Gradinaru is the principal investigator.

Additional Caltech authors on the paper, "Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain," are Sripriya Ravindra Kumar, Ken Y. Chan, Abhik Banerjee, Wei-Li Wu, and Bin Yang, as well as former Caltech students Piers L. Pravdo and Bryan P. Simpson. Nina Huber and Sergiu P. Pasca of Stanford University School of Medicine are also coauthors. The work was supported by funding from the Hereditary Disease Foundation and the Caltech-City of Hope Biomedical Initiative, a National Institutes of Health (NIH) Director's New Innovator Award, the NIH's National Institute of Aging and National Institute of Mental Health, the Beckman Institute, and the Gordon and Betty Moore Foundation.

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Kimm Fesenmaier
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Delivering Genes Across the Blood-Brain Barrier
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Caltech biologists have developed a vector capable of noninvasive delivery of genetic cargo throughout the adult central nervous system.

Novel Calibration Tool Will Help Astronomers Look for Habitable Exoplanets

Promising new calibration tools, called laser frequency combs, could allow astronomers to take a major step in discovering and characterizing earthlike planets around other stars. These devices generate evenly spaced lines of light, much like the teeth on a comb for styling hair or the tick marks on a ruler—hence their nickname of "optical rulers." The tick marks serve as stable reference points when making precision measurements such as those of the small shifts in starlight caused by planets pulling gravitationally on their parent stars.

Yet today's commercially available combs have a significant drawback. Because their tick marks are so finely spaced, the light output of these combs must be filtered to produce useful reference lines. This extra step adds complexity to the system and requires costly additional equipment.

To resolve these kinds of issues, Caltech researchers looked to a kind of comb not previously deployed for astronomy. The novel comb produces easily resolvable lines, without any need for filtering. Furthermore, the Caltech comb is built from off-the-shelf components developed by the telecommunications industry.

"We have demonstrated an alternative approach that is simple, reliable, and relatively inexpensive," says paper coauthor Kerry Vahala, the Ted and Ginger Jenkins Professor of Information Science and Technology and Applied Physics as well as the executive officer for Applied Physics and Materials Science in Caltech's Division of Engineering and Applied Science. The kind of frequency comb used by the researchers previously has been studied in the Vahala group in a different application, the generation of high-stability microwaves.

"We believe members of the astronomical community could greatly benefit in their exoplanet hunting and characterization studies with this new laser frequency comb instrument," says Xu Yi, a graduate student in Vahala's lab and the lead author of a paper describing the work published in the January 27, 2016, issue of the journal Nature Communications.

Scientists first began widely using laser frequency combs as precision rulers in the late 1990s in fields like metrology and spectroscopy; for their work, the technology's developers (John L. Hall of JILA and the National Institute of Standards and Technology (NIST) and Theodor Hänsch of the Max Planck Institute of Quantum Optics and Ludwig Maximilians University Munich) were awarded half of the Nobel Prize in Physics in 2005. In astronomy, the combs are starting to be utilized in the radial velocity, or "wobble" method, the earliest and among the most successful methods for identifying exoplanets.

The "wobble" refers to the periodic changes in a star's motion, accompanied by starlight shifts owing to the Doppler effect, that are induced by the gravitational pull of an exoplanet orbiting around the star. The magnitude of the shift in the starlight's wavelength—on the order of quadrillionths of a meter—together with the period of the wobble can be used to determine an exoplanet's mass and orbital distance from its star. These details are critical for assessing habitability parameters such as surface temperature and the eccentricity of the exoplanet's orbit. With exoplanets that pass directly in front of (or "transit") their host star, allowing their radius to be determined directly, it is even possible to determine the bulk composition—for example, if the planet is built up primarily of gas, ice, or rock. 

In recent years, so-called mode-locked laser combs have proven useful in this task. These lasers generate a periodic stream of ultrashort light pulses to create the comb. With such combs, however, approximately 49 out of every 50 tick marks must be blocked out. This requires temperature- and vibration-insensitive filtering equipment.

The new electro-optical comb that Vahala and his team studied relies on microwave modulation of a continuous laser source, rather than a pulsed laser. It produces comb lines spaced by tens of gigahertz. These lines have from 10 to 100 times wider spacing than the tick marks of pulsed laser combs.

To see how well a prototype would work in the field, the researchers took their comb to Mauna Kea in Hawaii. In September 2014, the instrument was tested at the NASA Infrared Telescope Facility (IRTF); in March 2015, it was tested with the Near Infrared Spectrometer on the W. M. Keck Observatory's Keck II telescope with the assistance of UCLA astronomer Mike Fitzgerald (BS '00) and UCLA graduate student Emily Martin, coauthors on the paper. The researchers found that their simplified comb (the entire electro-optical comb apparatus requires only half of the space available on a standard 19-inch instrumentation rack) provided steady calibration at room temperature for more than five days at IRTF. The comb also operated flawlessly during the second test—despite having been disassembled, stored for six months, and reassembled.

"From a technological maturity point of view, the frequency comb we have developed is already basically ready to go and could be installed at many telescopes," says paper coauthor Scott Diddams of NIST.

The Caltech comb produces spectral lines in the infrared, making it ideal for studying red dwarf stars, the most common stars in the Milky Way. Red dwarf stars are brightest in infrared wavelengths. Because red dwarfs are small, cool, and dim, planets orbiting these types of stars are easier to detect and analyze than those orbiting hotter sun-like stars. NASA's Kepler space observatory has shown that almost all red dwarf stars host planets in the range of one to four times the size of Earth, with up to 25 percent of these planets located in the temperate, or "habitable," zone around their host stars. Thus, many astronomers predict that red dwarfs provide the best chance for the first discovery of a world capable of supporting life.

"Our goal is to make these laser frequency combs simple and sturdy enough that you can slap them onto every telescope, and you don't have to think about them anymore," says paper coauthor Charles Beichman, senior faculty associate in astronomy and the executive director of the NASA ExoPlanet Science Institute at Caltech. "Having these combs routinely available as a modest add-on to current and future instrumentation really will expand our ability to find potentially habitable planets, particularly around very cool red dwarf stars," he says.

The research team is planning to double the frequency of the prototype comb's light output—now centered around 1,550 nanometers, in the infrared—to reach into the visible light range. Doing so would allow the comb also to calibrate spectra from sun-like stars, whose light output is at shorter, visible wavelengths, and thus seek out planets that are Earth's "twins."

Other authors of the paper are Jiang Li, a visitor in applied physics and materials science, graduate students Peter Gao and Michael Bottom, and scientific research assistant Elise Furlan, all from Caltech; Stephanie Leifer, Jagmit Sandhu, Gautam Vasisht, and Pin Chen of JPL; Peter Plavchan (BS '01), formerly at Caltech and now a professor at Missouri State University; G. Ycas of NIST; Jonathan Gagne of the University of Montréal; and Greg Doppmann of the Keck Observatory.

The paper is titled "Demonstration of a near-IR line-referenced electro-optical laser frequency comb for precision radial velocity measurements in astronomy." The research performed at Caltech and JPL was funded through the President's and Director's Fund Program, and the work at NIST was funded by the National Science Foundation. 

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Novel Tool Aids Exoplanet Hunt
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Researchers have developed a laser frequency comb that expands the ability to find habitable worlds.

Where Is Solar Energy Headed?

In a new paper in ScienceNate Lewis, the George L. Argyros Professor of Chemistry at Caltech, reviews recent developments in solar-energy utilization and looks at some of the challenges and opportunities that lie ahead in the research and development of solar-electricity, solar-thermal, and solar-fuels technologies. Read the full paper.

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Caltech Researchers Find Evidence of a Real Ninth Planet

Caltech researchers have found evidence of a giant planet tracing a bizarre, highly elongated orbit in the outer solar system. The object, which the researchers have nicknamed Planet Nine, has a mass about 10 times that of Earth and orbits about 20 times farther from the sun on average than does Neptune (which orbits the sun at an average distance of 2.8 billion miles). In fact, it would take this new planet between 10,000 and 20,000 years to make just one full orbit around the sun.

The researchers, Konstantin Batygin and Mike Brown, discovered the planet's existence through mathematical modeling and computer simulations but have not yet observed the object directly.

"This would be a real ninth planet," says Brown, the Richard and Barbara Rosenberg Professor of Planetary Astronomy. "There have only been two true planets discovered since ancient times, and this would be a third. It's a pretty substantial chunk of our solar system that's still out there to be found, which is pretty exciting."

Brown notes that the putative ninth planet—at 5,000 times the mass of Pluto—is sufficiently large that there should be no debate about whether it is a true planet. Unlike the class of smaller objects now known as dwarf planets, Planet Nine gravitationally dominates its neighborhood of the solar system. In fact, it dominates a region larger than any of the other known planets—a fact that Brown says makes it "the most planet-y of the planets in the whole solar system."

Batygin and Brown describe their work in the current issue of the Astronomical Journal and show how Planet Nine helps explain a number of mysterious features of the field of icy objects and debris beyond Neptune known as the Kuiper Belt.

"Although we were initially quite skeptical that this planet could exist, as we continued to investigate its orbit and what it would mean for the outer solar system, we become increasingly convinced that it is out there," says Batygin, an assistant professor of planetary science. "For the first time in over 150 years, there is solid evidence that the solar system's planetary census is incomplete."

The road to the theoretical discovery was not straightforward. In 2014, a former postdoc of Brown's, Chad Trujillo, and his colleague Scott Sheppard published a paper noting that 13 of the most distant objects in the Kuiper Belt are similar with respect to an obscure orbital feature. To explain that similarity, they suggested the possible presence of a small planet. Brown thought the planet solution was unlikely, but his interest was piqued.

He took the problem down the hall to Batygin, and the two started what became a year-and-a-half-long collaboration to investigate the distant objects. As an observer and a theorist, respectively, the researchers approached the work from very different perspectives—Brown as someone who looks at the sky and tries to anchor everything in the context of what can be seen, and Batygin as someone who puts himself within the context of dynamics, considering how things might work from a physics standpoint. Those differences allowed the researchers to challenge each other's ideas and to consider new possibilities. "I would bring in some of these observational aspects; he would come back with arguments from theory, and we would push each other. I don't think the discovery would have happened without that back and forth," says Brown. " It was perhaps the most fun year of working on a problem in the solar system that I've ever had."

Fairly quickly Batygin and Brown realized that the six most distant objects from Trujillo and Sheppard's original collection all follow elliptical orbits that point in the same direction in physical space. That is particularly surprising because the outermost points of their orbits move around the solar system, and they travel at different rates.

"It's almost like having six hands on a clock all moving at different rates, and when you happen to look up, they're all in exactly the same place," says Brown. The odds of having that happen are something like 1 in 100, he says. But on top of that, the orbits of the six objects are also all tilted in the same way—pointing about 30 degrees downward in the same direction relative to the plane of the eight known planets. The probability of that happening is about 0.007 percent. "Basically it shouldn't happen randomly," Brown says. "So we thought something else must be shaping these orbits."

The first possibility they investigated was that perhaps there are enough distant Kuiper Belt objects—some of which have not yet been discovered—to exert the gravity needed to keep that subpopulation clustered together. The researchers quickly ruled this out when it turned out that such a scenario would require the Kuiper Belt to have about 100 times the mass it has today.

That left them with the idea of a planet. Their first instinct was to run simulations involving a planet in a distant orbit that encircled the orbits of the six Kuiper Belt objects, acting like a giant lasso to wrangle them into their alignment. Batygin says that almost works but does not provide the observed eccentricities precisely. "Close, but no cigar," he says.

Then, effectively by accident, Batygin and Brown noticed that if they ran their simulations with a massive planet in an anti-aligned orbit—an orbit in which the planet's closest approach to the sun, or perihelion, is 180 degrees across from the perihelion of all the other objects and known planets—the distant Kuiper Belt objects in the simulation assumed the alignment that is actually observed.

"Your natural response is 'This orbital geometry can't be right. This can't be stable over the long term because, after all, this would cause the planet and these objects to meet and eventually collide,'" says Batygin. But through a mechanism known as mean-motion resonance, the anti-aligned orbit of the ninth planet actually prevents the Kuiper Belt objects from colliding with it and keeps them aligned. As orbiting objects approach each other they exchange energy. So, for example, for every four orbits Planet Nine makes, a distant Kuiper Belt object might complete nine orbits. They never collide. Instead, like a parent maintaining the arc of a child on a swing with periodic pushes, Planet Nine nudges the orbits of distant Kuiper Belt objects such that their configuration with relation to the planet is preserved.

"Still, I was very skeptical," says Batygin. "I had never seen anything like this in celestial mechanics."

But little by little, as the researchers investigated additional features and consequences of the model, they became persuaded. "A good theory should not only explain things that you set out to explain. It should hopefully explain things that you didn't set out to explain and make predictions that are testable," says Batygin.

And indeed Planet Nine's existence helps explain more than just the alignment of the distant Kuiper Belt objects. It also provides an explanation for the mysterious orbits that two of them trace. The first of those objects, dubbed Sedna, was discovered by Brown in 2003. Unlike standard-variety Kuiper Belt objects, which get gravitationally "kicked out" by Neptune and then return back to it, Sedna never gets very close to Neptune. A second object like Sedna, known as 2012 VP113, was announced by Trujillo and Sheppard in 2014. Batygin and Brown found that the presence of Planet Nine in its proposed orbit naturally produces Sedna-like objects by taking a standard Kuiper Belt object and slowly pulling it away into an orbit less connected to Neptune.


A predicted consequence of Planet Nine is that a second set of confined objects should also exist. These objects are forced into positions at right angles to Planet Nine and into orbits that are perpendicular to the plane of the solar system. Five known objects (blue) fit this prediction precisely.
Credit: Caltech/R. Hurt (IPAC) [Diagram was created using WorldWide Telescope.]

But the real kicker for the researchers was the fact that their simulations also predicted that there would be objects in the Kuiper Belt on orbits inclined perpendicularly to the plane of the planets. Batygin kept finding evidence for these in his simulations and took them to Brown. "Suddenly I realized there are objects like that," recalls Brown. In the last three years, observers have identified four objects tracing orbits roughly along one perpendicular line from Neptune and one object along another. "We plotted up the positions of those objects and their orbits, and they matched the simulations exactly," says Brown. "When we found that, my jaw sort of hit the floor."

"When the simulation aligned the distant Kuiper Belt objects and created objects like Sedna, we thought this is kind of awesome—you kill two birds with one stone," says Batygin. "But with the existence of the planet also explaining these perpendicular orbits, not only do you kill two birds, you also take down a bird that you didn't realize was sitting in a nearby tree."

Where did Planet Nine come from and how did it end up in the outer solar system? Scientists have long believed that the early solar system began with four planetary cores that went on to grab all of the gas around them, forming the four gas planets—Jupiter, Saturn, Uranus, and Neptune. Over time, collisions and ejections shaped them and moved them out to their present locations. "But there is no reason that there could not have been five cores, rather than four," says Brown. Planet Nine could represent that fifth core, and if it got too close to Jupiter or Saturn, it could have been ejected into its distant, eccentric orbit.

Batygin and Brown continue to refine their simulations and learn more about the planet's orbit and its influence on the distant solar system. Meanwhile, Brown and other colleagues have begun searching the skies for Planet Nine. Only the planet's rough orbit is known, not the precise location of the planet on that elliptical path. If the planet happens to be close to its perihelion, Brown says, astronomers should be able to spot it in images captured by previous surveys. If it is in the most distant part of its orbit, the world's largest telescopes—such as the twin 10-meter telescopes at the W. M. Keck Observatory and the Subaru Telescope, all on Mauna Kea in Hawaii—will be needed to see it. If, however, Planet Nine is now located anywhere in between, many telescopes have a shot at finding it.

"I would love to find it," says Brown. "But I'd also be perfectly happy if someone else found it. That is why we're publishing this paper. We hope that other people are going to get inspired and start searching."

In terms of understanding more about the solar system's context in the rest of the universe, Batygin says that in a couple of ways, this ninth planet that seems like such an oddball to us would actually make our solar system more similar to the other planetary systems that astronomers are finding around other stars. First, most of the planets around other sunlike stars have no single orbital range—that is, some orbit extremely close to their host stars while others follow exceptionally distant orbits. Second, the most common planets around other stars range between 1 and 10 Earth-masses.

"One of the most startling discoveries about other planetary systems has been that the most common type of planet out there has a mass between that of Earth and that of Neptune," says Batygin. "Until now, we've thought that the solar system was lacking in this most common type of planet. Maybe we're more normal after all."

Brown, well known for the significant role he played in the demotion of Pluto from a planet to a dwarf planet adds, "All those people who are mad that Pluto is no longer a planet can be thrilled to know that there is a real planet out there still to be found," he says. "Now we can go and find this planet and make the solar system have nine planets once again."

The paper is titled "Evidence for a Distant Giant Planet in the Solar System."

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Kimm Fesenmaier
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Evidence of a Real Ninth Planet
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The giant planet, nicknamed Planet Nine, traces a bizarre, highly elongated orbit in the outer solar system.

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