Scientists Transform Lower-Body Cells into Facial Cartilage

Caltech scientists have converted cells of the lower-body region into facial tissue that makes cartilage, in new experiments using bird embryos. The researchers discovered a "gene circuit," composed of just three genes, that can alter the fate of cells destined for the lower bodies of birds, turning them instead into cells that produce cartilage and bones in the head.

The results, published in the June 24 issue of the journal Science, could eventually lead to therapies for conditions where facial bone or cartilage is lost. For example, cartilage destroyed in the nose due to cancer is particularly hard to replace. Understanding the genetic pathways that lead to the development of facial cartilage may help in future stem-cell therapies, where a patient's own skin cells could be transformed and used to repair the nose.

"When facial cartilage and bone is lost, from cancer or an accident, it has been difficult to replace," says Marianne Bronner, the Albert Billings Ruddock Professor of Biology at Caltech, and senior author of the Science report. "Our long term hope is that uncovering this gene circuit may be useful in reprogramming a patient's own stem cells to make facial cartilage."

The bones below our necks, referred to by scientists as the "long" bones, originate from a different source of tissue than the bones in our head. As embryos, we are born with a type of early tissue called the neural crest that forms along the entire body, from the head to the end of the spinal cord. Those neural crest cells which originate in the head, called cranial neural crest, differentiate into the cartilage and bone of our faces, including the jaws and skull. In contrast, the so-called trunk neural crest cells, forming below the neck, do not make cartilage or bone but instead turn into nerve cells and pigment cells elsewhere in our bodies. Bronner and her colleagues want to understand what genes regulate the development of cranial neural crest cells and enable them to make cartilage and bones in the head.

To this end, they divided the trunk and cranial neural crest cells of bird embryos into separate groups, and looked for differences in gene activity. Fifteen genes were initially identified as being turned on in only the cranial cells. The researchers chose six of these genes for further study. All six code for transcription factors—molecules that bind to DNA to turn on and off the expression of other genes. After studying how these factors interact with each other, the scientists focused on three, called Sox8, Tfap2b and Ets, that are part of the cranial neural crest circuit.

These three genes were then inserted into the bodies of developing bird embryos, in particular the trunk neural crest, using a technique called electroporation. In this method, electric current is applied to cells to open up pores through which molecules such as DNA may pass. Next, the researchers transplanted the altered trunk cells to the cranial region of the embryos. Five days later, the trunk cells were doing something entirely new: producing cartilage.

"Normally, these trunk cells will not make cartilage," says Bronner. "Introducing just three genes into these cells reprogrammed them to acquire the ability to do so."

Bronner said that she hopes other researchers will use this information for experiments in cell culture. By adding the new-found gene circuit, perhaps with other known factors, to skin cells in a petri dish it may be possible to turn them into cartilage-producing cells—a key next step in creating future therapies for facial bone and cartilage loss.

The first author of the Science paper, titled, "Reprogramming of avian neural crest axial identity and cell fate," is Marcos Simoes-Costa of Caltech. The research is funded by the National Institutes of Health and the Pew Fellows Program in Biomedical Sciences.

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Gravitational Waves Detected from Second Pair of Colliding Black Holes

The LIGO Scientific Collaboration and the Virgo collaboration identify a second gravitational wave event in the data from Advanced LIGO detectors

On December 26, 2015 at 03:38:53 UTC, scientists observed gravitational waves—ripples in the fabric of spacetime—for the second time.

The gravitational waves were detected 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.

Gravitational waves carry information about their origins and about the nature of gravity that cannot otherwise be obtained, and physicists have concluded that these gravitational waves were produced during the final moments of the merger of two black holes—14 and 8 times the mass of the sun—to produce a single, more massive spinning black hole that is 21 times the mass of the sun.

"It is very significant that these black holes were much less massive than those observed in the first detection," says Gabriela Gonzalez, LIGO Scientific Collaboration (LSC) spokesperson and professor of physics and astronomy at Louisiana State University. "Because of their lighter masses compared to the first detection, they spent more time—about one second—in the sensitive band of the detectors. It is a promising start to mapping the populations of black holes in our universe."

During the merger, which occurred approximately 1.4 billion years ago, a quantity of energy roughly equivalent to the mass of the sun was converted into gravitational waves. The detected signal comes from the last 27 orbits of the black holes before their merger. Based on the arrival time of the signals—with the Livingston detector measuring the waves 1.1 milliseconds before the Hanford detector—the position of the source in the sky can be roughly determined.

"In the near future, Virgo, the European interferometer, will join a growing network of gravitational wave detectors, which work together with ground-based telescopes that follow-up on the signals," notes Fulvio Ricci, the Virgo Collaboration spokesperson, a physicist at Istituto Nazionale di Fisica Nucleare (INFN) and professor at Sapienza University of Rome. "The three interferometers together will permit a far better localization in the sky of the signals."

The first detection of gravitational waves, announced on February 11, 2016, confirmed a major prediction of Albert Einstein's 1915 general theory of relativity, and marked the beginning of the new field of gravitational-wave astronomy.

The second discovery "has truly put the 'O' for Observatory in LIGO," says Caltech's Albert Lazzarini, deputy director of the LIGO Laboratory. "With detections of two strong events in the four months of our first observing run, we can begin to make predictions about how often we might be hearing gravitational waves in the future. LIGO is bringing us a new way to observe some of the darkest yet most energetic events in our universe."

"We are starting to get a glimpse of the kind of new astrophysical information that can only come from gravitational wave detectors," says MIT's David Shoemaker, who led the Advanced LIGO detector construction program.

Both discoveries were 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.

"With the advent of Advanced LIGO, we anticipated researchers would eventually succeed at detecting unexpected phenomena, but these two detections thus far have surpassed our expectations," says NSF Director France A. Córdova. "NSF's 40-year investment in this foundational research is already yielding new information about the nature of the dark universe."

Advanced LIGO's next data-taking run will begin this fall. By then, further improvements in detector sensitivity are expected to allow LIGO to reach as much as 1.5 to 2 times more of the volume of the universe. The Virgo detector is expected to join in the latter half of the upcoming observing run.

LIGO research is carried out by the LIGO Scientific Collaboration (LSC), a group of more than 1,000 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.

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 MTA 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.

The NSF provides most of the 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, the ARCCA cluster at Cardiff University, the University of Wisconsin-Milwaukee, and the Open Science Grid. Several universities designed, built, and tested key components and techniques for Advanced LIGO: The Australian National University, the University of Adelaide, the University of Western Australia, the University of Florida, Stanford University, Columbia University in the City of New York, and Louisiana State University. 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 Germany, and the University of the Balearic Islands in Spain.

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Gravitational Waves Detected a Second Time
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Live Webcast: LIGO, Virgo Scientists to Discuss Continued Search for Gravitational Waves

The latest research in the effort to detect gravitational waves will be discussed in a press briefing at the 228th meeting of the American Astronomical Society in San Diego, California. The public can view the briefing during the live webcast, scheduled to begin at 10:15 am Pacific Daylight Time on Wednesday, June 15, 2016. The panelists for the briefing are Caltech's David Reitze, executive director of LIGO; Gabriela González, LIGO Scientific Collaboration spokesperson, from Louisiana State University; and Fulvio Ricci, Virgo spokesperson, from the University of Rome Sapienza and the Istituto Nazionale di Fisica Nucleare in Rome.

The first detection of gravitational waves, announced on February 11, 2016, confirmed a major prediction of Albert Einstein's 1915 general theory of relativity, and marked the beginning of the new field of gravitational-wave astronomy.

LIGO, a system of two identical detectors located in Livingston, Louisiana, and Hanford, Washington, was constructed to detect the tiny vibrations from passing gravitational waves, was conceived and built by Caltech and MIT with funding from the National Science Foundation and contributions from other U.S. and international partners.

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Dietary Fiber and Microbes Change the Gel That Lines Our Gut

In the ongoing hustle and bustle of our intestines, where bacteria and food regularly intermingle, there is another substance that, to the surprise of researchers, has been found to rapidly change: the gel that lines the gut. A new Caltech study is the first to show how the structure of this gut gel, or mucus, can change in the presence of certain substances, such as bacteria and polymers—a class of long-chained molecules that includes dietary fiber.

The work, to be published online the week of June 13 in the Proceedings of the National Academy of Sciences, could lead to the development of new drugs or diets for intestinal conditions such as irritable bowel disease.

Our intestinal tracts are lined with a mucus gel that acts as a protective barrier between the insides of our bodies and the outside world. The gel lets in nutrients and largely blocks out bacteria, preventing infections. It also regulates how some drugs are delivered elsewhere in our bodies.

Researchers had previously studied how the gel can be damaged, for instance when bacteria feed on the gut's lining. The Caltech study is the first to look at the structure of the gel and how it morphs in the presence of other substances naturally found in the gut.

Performing their experiments in mice, the team tested the effects of polymers, which include dietary fiber as well as therapeutics such as medicines for constipation. The researchers fed some mice a diet rich in polymers and others (the controls) a polymer-free diet. Using a technique called confocal reflectance microscopy they measured the thickness of the gut gel and the degree to which the gel was compressed as a result of the consumed polymers. Mice given a high-polymer diet, they found, had a more compressed gel layer.

"The gel is like a sponge with holes that let material through," says the paper's lead author, Sujit Datta, a postdoctoral scholar in the laboratory of Rustem Ismagilov, Ethel Wilson Bowles and Robert Bowles Professor of Chemistry and Chemical Engineering. "We are seeing that polymers, including dietary fiber, can compress the gel, potentially making the holes smaller, and we think that this might offer protective benefits," Datta adds.

In addition, the researchers applied different kinds of polymers—including dietary fibers like pectin, found in apples—directly to the gel lining to test its response. All of the polymers tested compressed the gel layer.

"It's too early to draw any conclusions, but it may be that eating an apple a day will affect the shape of the lining in your gut," says Asher Preska Steinberg, a Caltech graduate student and coauthor of the study.

The researchers also found that dietary fiber and gut bacteria—which are part of a community of microorganisms collectively known as gut microbiota—can work together to influence how the gut gel changes shape. They performed the same polymer/fiber experiments in germ-free mice, which are mice carefully raised to not have any bacteria in their gut. The results showed that the polymers compressed the gut gels of these germ-free mice to a greater degree. This implies that species of bacteria in our gut that are known to break down polymers can weaken the compressing effect.

"We previously thought of the gel as a static structure, so it was unexpected to find an interplay between diet and gut microbiota that rapidly and dynamically changes the biological structures that protect a host," says Ismagilov.

Both dietary fiber and certain gut microbes have been linked to good health. Fiber has been shown to lower cholesterol and regulate blood sugar levels—factors in heart disease and diabetes, respectively. Meanwhile, some bacteria, including the good "probiotics," can help treat digestive disorders and may even play a beneficial role in mental health. For instance, a separate Caltech-led study found that probiotics can alleviate autism-like behaviors in mice—a finding that could potentially lead to new therapies for the disorder in humans.

The entire collection of bacteria in our gut can include 1,000 different species or more and weigh a total of three pounds. Exactly how these microscopic organisms influence our health, for good and bad, is an area of active research with many unanswered questions. The White House recently announced the National Microbiome Initiative, with federal funding worth $121 million, to investigate the mysteries of microbes not only living in our bodies but all over the planet. In addition, more than 100 nonfederal agencies have pledged money and support toward researching microbial communities.

"Our study gives biologists and scientists studying diseases of the gut something else to think about," says Datta. "Now they can take the structure of the gut mucus, and how it responds to its environment, into account."

This research was funded by the Defense Advanced Research Projects Agency (DARPA) and National Science Foundation.

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Microbes & Dietary Fiber Change the Gut Lining
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The study is the first to look at the structure of the gut's mucus gel lining and how it morphs in the presence of other substances naturally found in the gut.

Natural Quasicrystals May Be the Result of Collisions Between Objects in the Asteroid Belt

Naturally formed quasicrystals—crystal-like solids with supposedly impossible symmetries—are among the rarest structures on Earth. Only two have ever been found.

A team led by Paul Asimow (MS '93, PhD '97), professor of geology and geochemistry at Caltech, may have uncovered one of the reasons for that scarcity, demonstrating in laboratory experiments that quasicrystals could arise from collisions between rocky bodies in the asteroid belt with unusual chemical compositions.

A paper on their findings was published on June 13 in the advance online edition of the Proceedings of the National Academy of Sciences.

At an atomic level, crystals are both ordered and periodic, meaning that they have a defined geometric structure, with that structure repeating itself over and over. To grow such a repeating structure without the original organization breaking down, the crystal can only exhibit one of four types of rotational symmetry: two-fold, three-fold, four-fold, or six-fold.

The number refers to how many times an object will look exactly the same within a full 360-degree rotation about an axis. For example, an object with two-fold symmetry appears the same twice, or every 180 degrees; an object with three-fold symmetry appears the same three times, or every 120 degrees; and an object with four-fold symmetry appears the same four times, or every 90 degrees.

Prior to 1984, it was believed that it would be impossible for a crystal to grow with any other type of symmetry; no examples of crystals with other symmetries had been discovered in nature or grown in a lab. In that year, however, Princeton physicist Paul Steinhardt (BS '74) theorized a set of conditions under which other types of symmetry could potentially exist and Dan Shechtman of the Israel Institute of Technology published a paper announcing the creation of a crystal-like structure with a five-fold rotational symmetry.

These structures were ordered enough to produce recognizable diffraction patterns when shot with high-energy beams of electrons and X-rays—unlike disordered structures, which produce no patterns. However, the crystal-like structures were not periodic—that is, their organization shifted and changed as they grew. The materials were dubbed "quasiperiodic crystals," or "quasicrystals" for short.

Over the next few decades, researchers figured out how to manufacture more than 100 different varieties of quasicrystals by melting and homogenizing certain elements and then cooling them at very specific rates in the lab. Still, though, no naturally existing quasicrystals were known. Indeed, researchers suspected their formation would be impossible. That is because most lab-grown quasicrystals were metastable, meaning that the same combination of elements could arrange themselves into a crystalline structure using less energy.

Everything changed in the late 2000s, when Steinhardt and colleague Luca Bindi from the Museum of Natural History at the University of Florence (currently in the Faculty of the Department of Earth Sciences of the same University) found a tiny grain of an aluminum, copper, and iron mineral that exhibited five-fold symmetry. The grain came from a small sample of the Khatyrka meteorite, an extraterrestrial object known only from a few pieces found in Russia's Koryak Mountains. Steinhardt and his collaborators found a second natural quasicrystal from the same meteorite in 2015, confirming that the natural existence of quasicrystals was possible, just very rare.

A microscopic analysis of the meteorite indicated that it had undergone a major shock at some point in its lifetime before crashing to Earth – likely from a collision with another rocky body in space. Such collisions are common in the asteroid belt and release high amounts of energy.

Asimow and colleagues hypothesized that the energy released by the shock could have caused the quasicrystal's formation by triggering a rapid cycle of compression, heating, decompression, and cooling.

To test the hypothesis, Asimow simulated the collision between two asteroids in his lab. He took thin slices of minerals found in the Khatyrka meteorite and sandwiched them together in a sample case that resembles a steel hockey puck. He then screwed the "puck" to the muzzle of a four-meter-long, 20-mm-bore single-stage propellant gun, and blasted it with a projectile at nearly one kilometer per second, about equal to the speed of the fastest rifle-fired bullets.

It is important to note that those minerals included a sample of a metallic copper-aluminum alloy, which has only been found in nature in the Khatyrka meteorite.

After the sample was shocked with the propellant gun, it was sawed open, polished, and examined. The impact smashed the sandwiched elements together and, in several spots, created microscopic quasicrystals.

Armed with this experimental evidence, Asimow says he is confident that shocks are the source of naturally formed quasicrystals. "We know that the Khatyrka meteorite was shocked. And now we know that when you shock the starting materials that were available in that meteorite, you get a quasicrystal."

Sarah Stewart (PhD '02)—a planetary collision expert from the University of California, Davis, and reviewer of the PNAS paper—admits she was surprised by the findings. "If you had called me before the study and asked if this would work I would have said 'no way.' The astounding thing is that they did it so easily," she says. "Nature is crazy."

Asimow acknowledges that the experiments leave many questions unanswered. For example, it is unclear at what point the quasicrystal formed during the shock's pressure and temperature cycle. A bigger mystery, Asimow says, is the origin of the copper-aluminum alloy in the meteorite, which has never been seen elsewhere in nature.

Next, Asimow plans to shock various combinations of minerals to see what key ingredients are necessary for natural quasicrystal formation.

These results are published in a paper titled "Shock synthesis of quasicrystals with implications for their origin in asteroid collisions." In addition to Asimow, Steinhardt, and Bindi, other coauthors on the paper are Chi Ma, director of analytical facilities in the Geological and Planetary Sciences division at Caltech; Lincoln Hollister (PhD '66) and Chaney Lin from Princeton University; and Oliver Tschauner from the University of Nevada, Las Vegas. Their work was supported by the National Science Foundation (NSF), the University of Florence, and the NSF-Materials Research Science & Engineering Centers Program through New York University and the Princeton Center for Complex Materials.

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Experiment Points to Origin of Quasicrystals
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A Feeling Touch

Using funding from the BRAIN Initiative, Caltech biologists are developing neuroprosthetics to bring tactile sensations to the users of robotic arms.

Caltech biologist Richard Andersen is working to incorporate a sense of touch into the neural prosthetics he has been helping develop for years—devices implanted in the brain that allow a paralyzed patient to manipulate a robotic arm.

Andersen and colleagues first reported success of their original implant in early 2015. The team, led by Andersen, placed their prosthesis in the posterior parietal cortex, an area that controls the intent to move rather than controlling movement directly as previous experiments had done. This allowed Erik Sorto, a 35-year-old man who has been paralyzed from the neck down for more than 10 years, to use a robotic arm placed next to his body to perform a fluid hand-shaking gesture, play rock-paper-scissors, and even grasp a bottle of beer and bring it to his mouth for a sip—something he had long dreamed of doing.

This research on how to make a robotic arm move resulted in a 2015 National Science Foundation grant to Andersen from President Obama's Brain Research through Advancing Innovative Neurotechnology—or BRAIN—Initiative, as well as seed money from the California Blueprint for Research to Advance Innovations in Neuroscience (Cal-BRAIN) program, the California complement to the federal initiative, which gave out its first-ever monetary awards last year to a group of researchers that included Andersen.

Andersen is now using those Cal-BRAIN funds—designed to bring together interdisciplinary teams of scientists and engineers from diverse fields for fundamental brain research—to take his team's work to the next level. His hope is to enable people using robotic arms to literally regain their sense of touch—their ability to feel an object in their "hands."

For more on Andersen's work, read A Feeling Touch on E&S+

 

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Caltech biologists are developing neuroprosthetics to bring tactile sensations to the users of robotic arms.

When Beneficial Bacteria Knock But No One is Home

The community of beneficial bacteria that live in our intestines, known as the gut microbiome, are important for the development and function of the immune system. There has been growing evidence that certain probiotics—therapies that introduce beneficial bacteria into the gut—may help alleviate some of the symptoms of intestinal disorders such as Crohn's disease. By studying the interplay between genetic risk factors for Crohn's and the bacteria that populate the gut, researchers at Caltech have discovered a new potential cause for this disorder in some patients—information that may lead to advances in probiotic therapies and personalized medicine.

The results were published online in the May 5 edition of the journal Science.

Previously, scientists had found that patients with Crohn's disease often exhibit alterations in both their genome and their gut microbiome—the diverse collection of bacteria that reside in the intestine. More than 200 genes have been implicated as having a role in the susceptibility to Crohn's. For years, researchers in the field have believed that these are genes that normally function by sensing pathogenic bacteria and deploying an immune response to kill the unwanted microbes; when these genes are defective, the pathogenic bacteria survive, multiply in the gut, and lead to disease.

"While we believe that all of that is true, in this study we were curious to see if some of the genes that are important in sensing pathogenic bacteria may also be important in sensing beneficial bacteria to promote immune health," says the study's first author, Hiutung Chu, a postdoctoral scholar in biology and biological engineering at Caltech. "Typically, the signals from these beneficial commensal microbes promote anti-inflammatory responses that dampen inflammation in the gut. However, mutations in genes that sense and respond to pathogenic bacteria would also impair the response to the beneficial ones. So it's kind of a new spin on the existing dogma."

To figure this out, Chu and her colleagues in the laboratory of Sarkis Mazmanian, the Luis B. and Nelly Soux Professor of Microbiology, designed several experiments to study how genetic mutations might interrupt the immune-enhancing effects of a known beneficial bacterium, Bacteroides fragilis. The researchers tested their new theory by using B. fragilis to treat mice that had nonfunctional versions of two genes known to play a role in Crohn's disease risk, called ATG16L1 and NOD2.

The researchers found that if just one of these two genes was absent, the mice were unable to develop disease-protective immune cells called regulatory T cells in response to B. fragilis—and that even after treatment with B. fragilis, symptoms in an ATG16L1-deficient mouse model of intestinal disease remained unchanged.

Chu and Mazmanian then obtained blood samples from both healthy patients and patients with Crohn's disease at the Cedars-Sinai Medical Center in Los Angeles. "We could see that certain patients' immune cells responded to Bacteroides fragilis, while immune cells from other patients didn't respond at all," Chu says. "Because the cells from Cedars had already been genotyped, we were able to match up our results with the patients' genotypes: immune cells from individuals with the protective version of ATG16L1 responded to the treatment, but cells from patients who had the mutated version of the gene showed no anti-inflammatory response to B. fragilis."

Mazmanian says the results suggest that the faulty versions of these genes may cause Crohn's disease in two different ways: by being unable to assist in destroying pathogenic bacteria and by preventing the beneficial immune signals usually elicited by "good" bacteria. "What Hiutung has shown is that there are specific bacteria in the human microbiome that appear to utilize the pathways that are encoded by these genes—genes normally involved in killing bacteria—to send beneficial signals to the host," he says.

This work reveals the important relationship between the genome and the microbiome—and it may also one day be used to improve the use of probiotics in clinical trials, Mazmanian says. "For example, our previous work has suggested using B. fragilis as a probiotic treatment for certain disorders. What this new study suggests is that there are certain populations that wouldn't benefit from this treatment because they have this genetic predisposition," he notes. "Right now, clinical trials don't do a good job of identifying which patients might respond best to treatment, but our experiments in mouse models suggest that, conceptually, you could design clinical trials that are more effective."

The research described in the paper, "Gene-Microbiota Interactions Contribute to the Pathogenesis of Inflammatory Bowel Disease," was funded by the National Institutes of Health, the Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, the Lupus Research Institute, the European Union, the Crohn's and Colitis Foundation of America, the Leona M. and Harry B. Helmsley Charitable Trust, and the Heritage Medical Research Institute.

In addition to Chu and Mazmanian, other Caltech coauthors include former graduate students Arya Khosravi (PhD '14) and Yue Shen (PhD '12); research technician assistants Indah Kusumawardhani and Alice Kwon; and Wei-Li Wu, a postdoctoral scholar in biology and biological engineering. Coauthors from other institutions include: Anilton Vasconcelos and Peter Ernst from UC San Diego; Larissa Cunha and Douglas Green from St. Jude Children's Research Hospital in Memphis; Anne Mayer, Amal Kambal, and Herbert Virgin from the Washington University School of Medicine in St. Louis; Stephan Targan and Dermot McGovern from Cedars-Sinai Medical Center; and Ramnik Xavier from Harvard Medical School.

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Michael Watkins Named Next JPL Director

Michael M. Watkins, the Clare Cockrell Williams Centennial Chair in Aerospace Engineering and Director of the Center for Space Research at The University of Texas at Austin, has been appointed director of the Jet Propulsion Laboratory and vice president at Caltech, the Institute announced today. 

Watkins will formally assume his position on July 1, 2016. He succeeds Charles Elachi, who will retire as of June 30, 2016, and move to the Caltech faculty.   

Watkins is an internationally recognized scientist and engineer. Prior to assuming his current position at The University of Texas in 2015, he worked at JPL for 22 years, where he held leadership roles on some of NASA's highest-profile missions. Watkins served as mission manager and mission system manager for the Mars Science Laboratory Curiosity Rover; led review or development teams for several missions including the Cassini, Mars Odyssey, and Deep Impact probes; and was the project scientist leading science development for the GRAIL moon-mapping satellites, the GRACE Earth science mission, and the GRACE Follow-On mission, scheduled for launch in 2017. He last served at JPL as manager of the Science Division, and chief scientist for the Engineering and Science Directorate.

"Michael's record of successful mission leadership and impressive management skills quickly distinguished him as a leading candidate for this position," says Caltech president Thomas F. Rosenbaum, the Sonja and William Davidow Presidential Chair and professor of physics. "As JPL director, Michael will build upon the laboratory's outstanding achievements in planetary exploration and earth science, strengthening the connections between Caltech's campuses and partnering with NASA to deliver highly complex and nuanced missions."

"I've known Mike Watkins for more than twenty years now," Elachi says. "Mike has played important and varying roles in a number of important JPL areas. His intimate knowledge of the lab and staff, combined with his highly diversified set of skills and knowledge base in science and engineering, will serve JPL very well in the years to come."

A committee composed of Caltech trustees, faculty, senior administrative leaders, and a member of the JPL executive council conducted an extensive search and recommended Watkins to Caltech's president.

Watkins holds a Bachelor's degree, Master's degree, and PhD in aerospace engineering from The University of Texas at Austin. He has published broadly in both engineering and science, contributed more than 100 conference presentations, and has served on the boards of numerous international scientific and engineering societies.

"JPL has such a talented and deeply committed staff," says Watkins. "It is a privilege to have this opportunity to lead the laboratory to even greater discoveries. I look forward to working with my colleagues on campus and across NASA to forge new directions in space exploration and earth science."

 

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Michael M. Watkins has been appointed director of the Jet Propulsion Laboratory and vice president at Caltech, the Institute announced today.

The Global History of Space Exploration

When talking about the history of space exploration, people are often quick to reference the Soviet and U.S. victories of the 1950s and 1960s, such as Sputnik and the Apollo program. However, these memorable advances are only a slice of a broader global history that includes significant contributions from dozens of nations, including many within the developing world. To science historian Asif Siddiqi—who specializes in the history of space exploration—these lesser-known stories of the global space race are just as interesting.

"For a long time, historians have said, 'Science is global!' but their claims were largely theoretical," Siddiqi says. "I'm interested in empirical examples of the global circulation of scientific knowledge and expertise, and one way I wanted to track this was through examples of leftover infrastructure from space exploration."

A professor of history at Fordham University, Siddiqi is this year's Eleanor Searle Visiting Professor of History at Caltech and The Huntington Library. The Searle visiting professorship is offered every year to a historian who wishes to conduct research in the Huntington's collections and teach courses in the Division of the Humanities and Social Sciences at Caltech.

"This professorship is a very wonderful opportunity for people in the middle of their careers to take a year off to start some new projects," he says.

Siddiqi has used this time, which continues until the end of the academic year, to focus his work on the history and impact of India's space program. "I'm interested in how developing nations allocated resources for very high-technology projects, despite their apparent social and economic problems. I wanted to look at India because it is a country with some obvious societal inequalities, but at the same time, they also prioritized this very modern technology. So I'm looking at the Indian space program through that lens," he says.

Siddiqi believes that one reason the Indian government initially became interested in space exploration was an urge to modernize after becoming independent from Great Britain in 1947. "Things like space exploration and nuclear energy were markers of the modern world, and they didn't want to have to spend 200 years trying to play catch up with the Western countries," he says. "That urge to 'leapfrog' over the West, often framed in terms of the modernization theory of the 1960s, gets manifested in a kind of fixation on certain things, and space was the most cutting-edge thing at the time."

The Indian government was also motivated by the introduction of technologies, developed by NASA, that the American government gave to other countries—such as India—in an effort to gain allies during the Cold War, Siddiqi says. The countries could keep these millions of dollars of scientific equipment and materials at no cost, allowing them to build an infrastructure for space exploration, with one unspoken but implicit caveat: they had to agree that, politically speaking, they would side with the U.S. against the Soviet Union.

Siddiqi also wanted to investigate how India's commitment to space exploration had an impact on those people not involved with science or politics. For instance, the Searle professorship allowed Siddiqi to travel to a small fishing village on the southern tip of India, to see how the space race impacted the local community.

"It turns out that this village's location intersects with a particular cosmic ray phenomenon that only happens around the magnetic equator," he says. The phenomenon, called the equatorial electrojet, results when solar winds cause an intensification of the Earth's magnetic field in a small patch directly above equatorial regions, including the Indian Ocean.

Because of this phenomenon, top scientists from around the world wanted to build an observatory in the village to study it. The Indian government got behind the plan, insisting that the international scientists leave behind all of their expensive equipment when they left, infrastructure which was later used for their space program. However, making room for the observatory also meant that the entire local fishing village would have to be packed up and relocated.

"One of my goals in this project was to recover the history of the Catholic fishing community that lived there for centuries, but had to be moved," Siddiqi says.

He was also interested in what it was like for the international community of scientists that was created on the former site of the fishing village. "It was 1963—the height of the Cold War—and there were scientists from the U.K., America, Russia, Germany, Japan, and all over the world working in this remote village," he notes, pointing out how unusual such a collaboration was during the Cold War.

The observatory only lasted a few decades, as expanding capabilities of satellites eventually made the ground-based technologies obsolete for these types of studies. But it had a lasting impact.

"The cosmic phenomenon above this Indian fishing village was a total accident of geography, and that's what was interesting about that story," Siddiqi says. "However, there are many more stories like that across the global landscape. Our narrative of the space race is mostly about astronauts and the moon, and maybe a little bit of deep-space exploration, such as Mars. But in my work, I hope to shed some light on some of these other types of contributions on the earth that are largely forgotten."

Siddiqi recently presented a summary of this work in a lecture at The Huntington Library titled, "A Different Space: NASA in the Postcolonial World."

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The Global History of Space Exploration
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Mapping Neurons to Improve the Treatment of Parkinson's

Because billions of neurons are packed into our brain, the neuronal circuits that are responsible for controlling our behaviors are by necessity highly intermingled. This tangled web makes it complicated for scientists to determine exactly which circuits do what. Now, using two laboratory techniques pioneered in part at Caltech, Caltech researchers have mapped out the pathways of a set of neurons responsible for the kinds of motor impairments—such as difficulty walking—found in patients with Parkinson's disease.

The work—from the laboratory of Viviana Gradinaru (BS '05), assistant professor of biology and biological engineering—was published on April 20 in the journal Neuron.

In patients with Parkinson's disease, gait disorders and difficulty with balance are often caused by the degeneration of a specific type of neuron—called cholinergic neurons—in a region of the brainstem called the pedunculopontine nucleus (PPN). Damage to this same population of neurons in the PPN is also linked to reward-based behaviors and disorders, such as addiction.

Previously, researchers had not been able to untangle the neural circuitry originating in the PPN to understand how both addictions and Parkinson's motor impairments are modulated within the same population of cells. Furthermore, this uncertainty created a barrier to treating those motor symptoms. After all, deep brain stimulation—in which a device is inserted into the brain to deliver electrical pulses to a targeted region—can be used to correct walking and balance difficulties in these patients, but without knowing exactly which part of the PPN to target, the procedure can lead to mixed results.

"The circuits responsible for controlling our behaviors are not nicely lined up, where this side does locomotion and this side does reward," Gradinaru says, and this disordered arrangement arises from the way neurons are structured. Much as a tree extends into the ground with long roots, neurons are made up of a cell body and a long string-like axon that can diverge and project elsewhere into different areas of the brain. Because of this shape, the researchers realized they could follow the neuron's "roots" to an area of the brain less crowded than the PPN. This would allow them to more easily look at the two very different behaviors and how they are implemented.

Cheng Xiao, a senior research scientist at Caltech and first author on the study, began by mapping the projections of the cholinergic neurons in the PPN of a rat using a technique developed by the Gradinaru lab called Passive CLARITY Technique, or PACT. In this technique, a solution of chemicals is applied to the brain; the chemicals dissolve the lipids in the tissue and render that region of the brain optically transparent—see-through, in other words—and able to take up fluorescent markers that can label different types of neurons. The researchers could then follow the path of the PPN neurons of interest, marked by a fluorescent protein, by simply looking through the rest of the brain.

Using this method, Gradinaru and Xiao were able to trace the axons of the PPN neurons as they extended into two regions of the midbrain: the ventral substantia nigra, a landmark area for Parkinson's disease that had been previously associated with locomotion; and the ventral tegmental area, a region of the brain that had been previously associated with reward.

Next, the researchers used an electrical recording technique to keep track of the signals sent by PPN neurons—confirming that these neurons do, in fact, communicate with their associated downstream structures in the midbrain. Then, the scientists went on to determine how this specific population of neurons affects behavior. To do this, they used a technique that Gradinaru helped develop called optogenetics, which allows researchers to manipulate neural activities—in this case, by either exciting or inhibiting the PPN neural projections in the midbrain—using different colors of light.

Using the optogenetic approach in rats, the researchers found that exciting the neuronal projections in the ventral substantia nigra would stimulate the animal to walk around its environment; by contrast, they could stop the animal's movement by inhibiting these same projections. Furthermore, they found that they could stimulate reward-seeking behavior by exciting the neuronal projections in the ventral tegmental area, but could cause aversive behavior by inhibiting these projections.

"Our results show that the cholinergic neurons from the PPN indeed have a role in controlling both behaviors," Gradinaru says. "Although the neurons are very densely packed and intermingled, these pathways are, to some extent, dedicated to very specialized behaviors." Determining which pathways are associated with which behaviors might also improve future treatments, she adds.

"In the past it's been difficult to target treatment to the PPN because the specific neurons associated with different behaviors are intermingled at the source—the PPN. Our results show that you could target the axonal projections in the substantia nigra for movement disorders and projections in the ventral tegmental area for reward disorders, as addiction is," Gradinaru says. In addition, she notes, these projections in the midbrain are much easier to access surgically than their source in the PPN.

Although this new information could inform clinical treatments for Parkinson's disease, the PPN is only one region of the brain and there are many more important examples of connectivity that need to be explored, Gradinaru says. "These results highlight the need for brain-wide functional and anatomical maps of these long-range neuronal projections; we've shown that tissue clearing and optogenetics are enabling technologies in the creation of these maps."

These results are published in a paper titled, "Cholinergic mesopontine signals govern locomotion and reward through dissociable midbrain pathways." In addition to Gradinaru and Xiao, other Caltech coauthors include Jounhong Ryan Cho, Chunyi Zhou, Jennifer Treweek, Ken Chan, Sheri McKinney, and Bin Yang. The work was supported by the National Institutes of Health, the Heritage Medical Research Institute, the Pew Charitable Trust, the Michael J. Fox Foundation, and the Sloan Foundation; the Beckman Institute supports the Resource Center on CLARITY, Optogenetics, and Vector Engineering (CLOVER) for technology development and broad dissemination.

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Mapping Neurons to Improve Parkinson's
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Caltech researchers have mapped out a circuit of neurons responsible for motor impairment in patients with Parkinson's disease.

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