Traveling with Purpose

Biologist spends summer vacation volunteering in India

Pamela Bjorkman has been studying HIV at Caltech since 2005. In the lab, she has made significant gains in the fight against the virus, developing antibodies that neutralize most strains. But years spent at the bench were beginning to make her feel disconnected from the possible impact of her work. So this summer she visited India, spending time with HIV-positive women and others who are at risk.

"What I wanted to do was see the real side of HIV, where it affects people," says Bjorkman, the Max Delbrück Professor of Biology and an investigator with the Howard Hughes Medical Institute. "We work in the lab where we have no contact with HIV-infected people—the human impact of the disease is very removed from what we think about in our work."

This was not her first trip to the nation of over 1.2 billion people, where nearly 30 percent of the population lives in poverty. She first visited in 1985 and returned with her teenage daughter in 2008 to work at an orphanage in the Jaipur area called Udayan. The home for children is part of an umbrella organization called Vatsalya that also runs an HIV-education program for female sex workers, among other projects aimed at empowering women and teaching street children vocational skills.

"The orphanage is really incredible," says Bjorkman, whose daughter accompanied her on her most recent trip as well. "There are an estimated 18 million children living on the street in India—a lot who are not actually orphans, but on the street anyway. The organization takes in as many children as it can—around 60—and those kids are never adopted. When they come to the orphanage, the group there becomes their family."

The mission of the organization—founded in 1995 by Jaimala and Hitesh Gupta, both of whom have backgrounds in public health—is to "provide a caring environment where our disadvantaged and vulnerable people can develop their capabilities with dignity." The orphanage is a nearly self-sufficient compound that includes a school, a farm, a garden, and dormitories. They even have a psychologist who visits with the children, many of whom suffered abuse at very young ages.

"It's really an amazing place," says Bjorkman. "Here these kids are, all living with the most horrible back stories, and they are full of joy and respectful and helpful. It makes you realize how incredibly privileged we are here in Pasadena and that we take a lot for granted."

Bjorkman and her daughter stayed at Udayan for two weeks each time they visited, helping to teach the children English and math, participating in art and dance projects, and helping with gardening and cooking. This summer, Bjorkman also traveled to Ajmer, where the group's HIV-education program is located. There, she met with women struggling with the stigma of HIV, particularly because they rely on sex work to support their children and send them to private school; public schools in many impoverished areas of India are notoriously bad.

"The organization identifies women in the community who are sex workers and are interested in learning some other trade, or who need help because of HIV infection," she explains. "The terrible thing is that when they find out they are HIV infected, many of the women start working more because their futures are more uncertain.  Plus, they hesitate to take medication because if anyone finds out that they are positive, they will lose customers." 

The organization provides counseling, runs a female condom education program, offers training classes for those wanting to become proficient at another job, and works to get HIV-positive women on antiretroviral medications. While visiting with the women, Bjorkman talked with them about how the virus works and why it's so tough to treat once it's in the body.

"This is the reason that I'm doing the HIV research," she says. "It's not to get our own papers out first, it's to actually do something that might make a difference. Meeting the women put a lot of the competition and the unpleasantness associated with the rat race of science into perspective."

Bjorkman plans to return to India, but in the meantime she's doing all she can to raise awareness for Vatsalya and their various projects. Like any nonprofit, the organization could use monetary donations, but she hopes that her story inspires others at Caltech to donate their time. Anyone, she says, can volunteer through Vatsalya and receive room, board, and meals at the orphanage for a nominal daily donation.

"Caltech undergrad and grad students don't necessarily have that much money, but they may have time and this would be an amazing way to get to know another culture," she says. "These people are really doing a great job—both with the orphanage and with the HIV program that I had direct experience with. Once you see the way it works, it's really inspiring."

For more information on Vatsalya and the work they do, visit their website. Or contact Pamela Bjorkman to find out how you can become directly involved with this organization.  

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Katie Neith
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Caltech Biologist Named MacArthur Fellow

PASADENA, Calif.—Sarkis Mazmanian, a microbiology expert at the California Institute of Technology (Caltech) whose studies of human gut bacteria have revealed new insights into how these microbes can be beneficial, was named a MacArthur Fellow and awarded a five-year, $500,000 "no strings attached" grant. Each year, the John D. and Catherine T. MacArthur Foundation awards the unrestricted fellowships—also known as "genius" grants—to individuals who have shown "extraordinary originality and dedication in their creative pursuits and a marked capacity for self-direction," according to the foundation's website.

"I was in a state of shock when I heard the news," says Mazmanian, a professor of biology at Caltech, who was tricked into taking the award announcement call; he thought he was simply being added to a prescheduled conference call. "It's not the kind of thing you ever expect—I do what I do because I love science and it makes me happy, so this is terrific and a nice reward. At the same time, I never think of awards as goals of mine because they seem so unattainable. My goals are to make discoveries, so I was just in absolute disbelief."

Long before he was named a 2012 MacArthur Fellow, Mazmanian was showing the attributes that the foundation seeks to reward, particularly a capacity for self-direction. As a graduate student in the in the early 2000s, he decided to stray from the normal path of study and try something new. 

"I had been studying microbial pathogenesis—or bacteria that make us sick—which is what 99.9 percent of the field of microbiology does to this day," says Mazmanian. "Toward the end of my PhD, I decided that I wanted to study organisms that didn't necessarily cause disease, but were associated with our bodies. Ten years ago, this was completely on the fringe of science—we knew that the organisms existed in our intestines and all over our bodies, but had no idea what they were doing."  

Today, Mazmanian's work examines some of the trillions of bacteria living in our bodies that make up complex communities of microbes and regulate processes like digestion and immunity. His main focus is to understand how "good" bacteria promote human health—work that has transformed a quickly evolving field of research that is investigating the connection between gut bacteria and their relationship to both disease and health.

His research helped lay the groundwork for the Human Microbiome Project (HMP), an initiative of the National Institutes of Health that aims to characterize, for the first time, "the microbial communities found at several different sites on the human body, including nasal passages, oral cavities, skin, gastrointestinal tract, and urogenital tract, and to analyze the role of these microbes in human health and disease," according to the HMP website.

 

His laboratory was the first to demonstrate that specific gut bacteria direct the development of the mammalian immune system and provide protection from intestinal diseases. This means, he says, that fundamental aspects of health are absolutely dependent on microbial interaction within our bodies. In addition, he says that many disorders whose incidences are increasing in Western countries—such as inflammatory bowel disease, multiple sclerosis, and asthma—involve a common immunologic defect believed to be caused by the absence of intestinal bacteria. An understanding of the beneficial immune responses promoted by gut bacteria may lead to the development of natural therapeutics for immunologic and perhaps neurologic diseases, says Mazmanian.

"This award is extremely well-deserved—Sarkis has revolutionized the way we think about the interactions between microorganisms and people," says Stephen L. Mayo, William K. Bowes Jr. Foundation Chair of Caltech's Division of Biology, and Bren Professor of Biology and Chemistry. "His research has had an important impact in making the connection between personal hygiene and the immune system, and even neurological diseases like autism."

When the award announcement went public, Mazmanian was in Armenia, his native homeland, teaching a one-week course on host-microbial interaction to PhD students at a molecular biology institute. He travels to the country once a year to volunteer his services. The timing, he says, couldn't be better, as he hopes to use some of the prize money to develop an international educational outreach program.

"I think that when you have a windfall like this, the least you can do is help people who are in need," says Mazmanian, who credits the members of his lab for his research success. "In many countries, they are in need of education and resources, like lab equipment, text books, you name it. It would be a terrific if I could use the money to help advance science in countries where there is hardship."

Mazmanian received his bachelor's degree in 1995 and his PhD in microbiology in 2002, both from UCLA. Following a postdoctoral fellowship at Harvard, he joined the Caltech faculty as an assistant professor in 2006. In 2012, he was promoted to professor of biology. In 2011, Mazmanian was the recipient of a Burroughs Welcome Fund award for research in the pathogenesis of infectious disease, and in 2008 he was awarded a Searle Scholarship and was named one of Discover magazine's "20 Best Brains Under 40," which highlighted young innovators in science.

This year's crop of 23 Fellows includes stringed-instrument bow maker Benoît Rolland and mathematician Maria Chudnovsky; Mazmanian joins the ranks of Caltech's previous MacArthur Fellows, including 2010 awardee John Dabiri.

For more information on the 2012 MacArthur Fellows, visit the foundation website at www.macfound.org.

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Katie Neith
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Biologist Wins "Genius" Grant
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Mars Rover Finds Evidence of Ancient Streambed

An ankle- or hip-deep stream once flowed with force across the surface of Mars in the very spot where NASA's Curiosity rover is currently exploring. The finding, announced by members of the project's science team today at the Jet Propulsion Laboratory (JPL), provides new information about a once wet environment in Gale Crater, the ancient impact crater where the rover touched down in early August.

Using Curiosity's mast camera to analyze two rock outcrops known as Hottah and Link, the team has identified a tilted block of an ancient streambed—a layer of conglomerate rock, which is made up of stones of different sizes and shapes cemented together.

"Curiosity's discovery of an ancient streambed at Gale Crater provides confirmation of the decades-old hypothesis that Mars once had rivers that flowed across its surface," says John Grotzinger, the mission's project scientist and the Fletcher Jones Professor of Geology at Caltech. "This is the starting point for our mission to explore ancient, potentially habitable environments, and to decode the early environmental history of Mars."

The sizes of the gravels in the conglomerate rock suggest that the stream once flowed at a rate of about a meter per second. The discovery marks the first time scientists have identified gravel that was once transported by water on Mars.

In coming weeks and months, the team plans to use all of Curiosity's analytical instruments to study these types of rocks. And Grotzinger points out, "Finding geological evidence for past water is a prerequisite to beginning geochemical measurements that inform analysis of ancient potentially habitable environments. Curiosity has the most sophisticated and comprehensive suite of geochemical instruments ever flown to Mars."

For more about the finding, read the full JPL release.

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Kimm Fesenmaier
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Ready for Your Close-Up?

Caltech study shows that the distance at which facial photos are taken influences perception

PASADENA, Calif.—As the saying goes, "A picture is worth a thousand words." For people in certain professions—acting, modeling, and even politics—this phrase rings particularly true. Previous studies have examined how our social judgments of pictures of people are influenced by factors such as whether the person is smiling or frowning, but until now one factor has never been investigated: the distance between the photographer and the subject. According to a new study by researchers at the California Institute of Technology (Caltech), this turns out to make a difference—close-up photo subjects, the study found, are judged to look less trustworthy, less competent, and less attractive.

The new finding is described in this week's issue of the open-access journal PLoS One.

Pietro Perona, the Allen E. Puckett Professor of Electrical Engineering at Caltech, came up with the initial idea for the study. Perona, an art history enthusiast, suspected that Renaissance portrait paintings often featured subtle geometric warping of faces to make the viewer feel closer or more distant to a subject. Perona wondered if the same sort of warping might affect photographic portraits—with a similar effect on their viewers—so he collaborated with Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology, and CNS graduate student Ronnie Bryan (PhD '12) to gather opinions on 36 photographs representing two different images of 18 individuals. One of each pair of images was taken at close range and the second at a distance of about seven feet.

"It turns out that faces photographed quite close-up are geometrically warped, compared to photos taken at a larger distance," explains Bryan. "Of course, the close picture would also normally be larger, higher resolution and have different lighting—but we controlled for all of that in our study. What you're left with is a warping effect that is so subtle that nobody in our study actually noticed it. Nonetheless, it's a perceptual clue that influenced their judgments."

That subtle distance warping, however, had a big effect: close-up photos made people look less trustworthy, according to study participants. The close-up photo subjects were also judged to look less attractive and competent.

"This was a surprising, and surprisingly reliable, effect," says Adolphs. "We went through a bunch of experiments, some testing people in the lab, and some even over the Internet; we asked participants to rate trustworthiness of faces, and in some experiments we asked them to invest real money in unfamiliar people whose faces they saw as a direct measure of how much they trusted them."

Across all of the studies, the researchers saw the same effect, Adolphs says: in photos taken from a distance of around two feet, a person looked untrustworthy, compared to photos taken seven feet away. These two distances were chosen by the researchers because one is within, and the other outside of, personal space—which on average is about three to four feet from the body.

In some of the studies, the researchers digitally warped images of faces taken at a distance to artificially manipulate how trustworthy they would appear. "Once you know the relation between the distance warp and the trustworthiness judgment, you could manipulate photos of faces and change the perceived trustworthiness,'' notes Perona.

He says that the group is now planning to build on these findings, using machine-vision techniques—technologies that can automatically analyze data in images. For example, one application would be for a computer program to have the ability to evaluate any face image in a magazine or on the Internet and to estimate the distance at which the photo was taken.

"The work might also allow us to estimate the perceived trustworthiness of a particular face image," says Perona. "You could imagine that many people would be interested in such applications—particularly in the political arena."

The study, "Perspective Distortion from Interpersonal Distance Is an Implicit Visual Cue for Social Judgments of Faces," was funded by grants from the National Institute of Mental Health and from the Gordon and Betty Moore Foundation.

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Katie Neith
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When Judging Portraits, Distance Matters
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Moving Targets

Caltech Biologists Gain New Insight into Migrating Cells

PASADENA, Calif.—At any given moment, millions of cells are on the move in the human body, typically on their way to aid in immune response, make repairs, or provide some other benefit to the structures around them. When the migration process goes wrong, however, the results can include tumor formation and metastatic cancer. Little has been known about how cell migration actually works, but now, with the help of some tiny worms, researchers at the California Institute of Technology (Caltech) have gained new insight into this highly complex task.

The team's findings are outlined this week online in the early edition of the Proceedings of the National Academy of Sciences (PNAS).

"In terms of cancer, we know how to find primary tumors and we know when they're metastatic, but we're missing information on the period in between when cells are crawling around, hanging out, and doing who knows what that leads to both of these types of diseases," says Paul Sternberg, Thomas Hunt Morgan Professor of Biology at Caltech, and corresponding author of the paper.

To learn more about those crawling, or migrating, cells, Sternberg looked at the animal he knows best—the tiny Caenorhabditis elegans, a common species of roundworm that he has been studying for many years. Despite their small size, the worms actually share quite a few genes with humans. 

"Migration is such a conserved process," says Mihoko Kato, a senior research fellow in biology at Caltech and a coauthor of the paper. "So whether it happens in C. elegans or in mammals, like humans, we think that many of the same genes are going to be involved."

Contained in each cell—be it human or worm—are thousands of genes, all of which have a special job, or jobs, to do. Of these genes, roughly one-third are active in a given cell. To see what genes are expressed during migration, Sternberg and Kato, along with Erich Schwarz, a research fellow in Sternberg's lab, studied a single cell, called the linker cell (LC), in the worms; during reproductive development, LCs travel almost the entire length of the worm's body.

Using high-powered microscopy, the team identified LCs at two intervals, 12 hours apart, during the worm's larval stage, and removed them from the animals. Then, using sequencing and computational analysis, they determined the genes that were actively expressed at these two migration time points. This method of study is called transcriptional profiling.

"By understanding the normal migration of a single cell, we can understand something about how the cells are programmed to navigate their environment," says Sternberg, who is also an investigator with the Howard Hughes Medical Institute. "Our view of cancer metastasis is that the tumor cells confront some obstacle and then they have to evolve to get through or around that obstacle. The way they probably do that is by using some aspect of the normal program that exists somewhere in the genome."

He says that learning more about different ways that cells migrate may lead to the development of new types of drugs that block this process by targeting specific genes. The team plans additional transcriptional profiling studies to obtain more detailed information about the functions of particular C. elegans genes involved in migration—and, eventually, of similar genes in higher organisms, including humans.

"We selected genes present in both worms and humans, but which have not been studied much before us," says Schwarz.  "Since we found that some of these genes help worm LCs migrate, we think each one may have a related human gene helping cells migrate, too."

"The nice thing about this technology is that you can use it with any cell type," adds Kato, who points out that their studies have already helped identify new functions for known genes possessed by both the worms and humans. "It's a similar process to do transcriptome profiling using human cells."

In addition to identifying drug targets, the team is also hoping to find a good signature, or molecular marker, for migrating cells. "This kind of information could be very useful diagnostically, to help identify cells that are doing things that they shouldn't be doing, or weird combinations of genes that shouldn't be expressed together, which is what a tumor cell might have," says Sternberg. "This work lays the foundation for really understanding what information is critically needed from mammalian cells for tumor cells to be able to migrate."

The study, "Functional transcriptomics of a migrating cell in Caenorhabditis elegans," was funded by the National Institutes of Health and the Howard Hughes Medical Institute.

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Moving Targets: Migrating Cells
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Martian Clay Minerals Might Have Much Hotter Origin

Ancient Mars, like Earth today, was a diverse planet shaped by many different geologic processes. So when scientists, using rovers or orbiting spacecraft, detect a particular mineral there, they must often consider several possible ways it could have been made.

Several such hypotheses have been proposed for the formation of clay minerals, which have been detected from orbit and are sometimes considered indicators that the surface has, in the past, been altered by liquid water. Now, publishing in the journal Nature Geoscience, a team of French and American scientists led by Alain Meunier of the Université de Poitiers and including Caltech's Bethany Ehlmann, has suggested a new, very different possibility.

Previously, planetary scientists considered two hypotheses—both offering the potential for once-habitable environments on Mars—that explain clay mineral formation. One holds that over long enough periods, contact with liquid water can alter igneous rock, such as basalt, producing clays; the other proposes that waters flowing through the martian subsurface can produce clays through a hydrothermal process.

In the new paper, the authors suggest that the clay minerals instead might have precipitated directly from scalding hot magmas.

"This new hypothesis is less exciting for astrobiology because life could not survive in those types of conditions," says Ehlmann, an assistant professor of planetary science at Caltech and a research scientist at the Jet Propulsion Laboratory. "But all three hypotheses need to be on the table as we consider a given clay-bearing deposit. Each hypothesis has a different implication for the history and habitability of ancient Mars."

Ehlmann says that scientists hope to use the Curiosity rover and its suite of instruments to study the clays found in sediments at Gale Crater—the impact crater that the robotic geologist was sent to explore. However, she notes, clays are typically found in even older igneous bedrock on Mars. Future rover missions would need to study clay formation in that ancient crust to rigorously test the various clay formation hypotheses. "There's more exploration that needs to be done before we understand all the mysteries of Mars," she says.

The Los Angeles Times recently spoke to Ehlmann about the new paper and its implications.

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Kimm Fesenmaier
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Hotter Origin Possible for Martian Clays
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Happy 35th Birthday, Voyager!

The spacecraft that just keep going and going

Today, September 5, marks the 35th anniversary of the launch of Voyager 1, which lifted off in 1977 on a Titan III–Centaur launch system just 16 days after its twin, Voyager 2. Now 11 billion and 9 billion miles from the sun, respectively, the spacecraft are the farthest-flung man-made objects, traveling every 100 days a distance equal to that between sun and Earth.

"We thought we could do this, but it is, in a certain sense, amazing," says Ed Stone, the mission's project scientist and the David Morrisroe Professor of Physics at Caltech. "After all, when the Voyagers were launched, the space age itself was only 20 years old."

Originally commissioned to last just four years, the Voyager mission created two identical spacecraft—with the hope that at least one would reach Jupiter and Saturn. As we now know, both Voyager spacecraft survived launch and the harsh radiation environment around Jupiter to relay close-up images and scientific measurements of the outer solar system's planets and their moons.

"There was much more out there to be discovered than we could have possibly imagined," says Andrew Ingersoll, an atmospheric scientist on the Voyager team and professor of planetary science at Caltech. "There were many heroes on the Voyager mission, but I like to say that the planets themselves were among those. The planets came through with amazing stuff."

Indeed, the Voyager spacecraft made a long list of discoveries on their tour of the outer planets. Some of Voyager 1's greatest hits include the finding that one of Jupiter's moons, Io, is home to eight active volcanoes spewing sulfur and oxygen, and that Saturn's largest moon, Titan, has a nitrogen atmosphere that lacks oxygen. For its part, Voyager 2 was the first spacecraft to visit and study Uranus and Neptune. At Uranus, it found that the planet's magnetic pole lies closer to the equator than the poles. And at Neptune, Voyager 2 found the fastest winds in the solar system.

"These are things we hadn't really thought about or imagined," Stone says. "With what I call our limited terracentric view, it was hard to realize how diverse nature really is. That's what Voyager revealed."

Today, the mission is officially known as the Voyager Interstellar Mission, acknowledging the fact that the robotic explorers are on a journey that is expected to one day take them out of our solar system and into interstellar space. When they will actually leave the sun's sphere of influence—an area called the heliosphere—no one can say, but mission scientists now say it appears to be only a matter of time before they do so. "But it could be several days, several weeks, or several years," Stone says.

Stone has served as the mission's project scientist since 1972. He describes Voyager as "a journey of a lifetime." These days, one of the first things he does every morning when he gets to his office in the Cahill Center for Astronomy and Astrophysics is to check the measurements of energetic particles detected by the Voyager 1 spacecraft. One of its instruments, the Cosmic Ray Subsystem, measures both high-energy particles that reach the spacecraft from outside the heliosphere and lower-energy particles that come from within the solar system. For the last seven years or so—since the spacecraft has been in a region known as the heliosheath—the number of lower-energy particles detected by Voyager 1's CRS has remained steady. Suddenly this past July, Stone says, that particle count dropped by about half, and then, after a few days, rose back up to normal. In August, Stone noticed the same odd phenomenon, but this time the number of particles decreased by nearly two-thirds before returning to normal.

"The particles inside the heliosphere are disappearing, episodically," Stone explains. "They haven't ever fully disappeared; the numbers have come back each time, so far. But evidently, the particles have been able to get out."

Coinciding with those dips are bumps—increases in the number of high-energy particles originating outside the heliosphere that are making their way inside. This decrease in one type of particle and increase in another indicates that Voyager 1 is nearing the edge of our solar system. Scientists are currently crunching data related to a third indicator—a switch in the direction of the magnetic field, which should occur when the spacecraft reaches interstellar space. The magnetic field within the heliosphere is created by the sun; the one outside the heliosphere is generated elsewhere in the galaxy. Therefore, it would be hard to imagine that the two are linked in any way, causing them to be oriented in the same direction. Also, indirect evidence suggests that unlike the magnetic field inside the heliosphere, which runs east-west with relation to the spin of the sun, the field outside is oriented more north-south.

What will Voyager find once it exits the solar system? "We're going to learn what's out there," Stone says. "There's clearly a magnetic field—we'll find out if it's what we think it is, how strong it is. We need to get out and measure it. That's what Voyager's taught us—go measure it."

The team still has about a dozen years to try to "get out" and make that measurement. Voyager is fueled by the natural radioactive decay of plutonium-238, which produces heat that thermocouples convert into electricity. Based on the plutonium's half-life, the Voyager team expects that they will need to begin shutting down instruments in 2020 and that they will turn off the last one by 2025.

Depending on when exactly that happens, the spacecraft will have spent close to 50 years exploring space and teaching scientists back on Earth new ways to think about the solar system and its surroundings. Reflecting back on his years of involvement with Voyager, Ingersoll says the mission pretty much taught him what science should be. "It taught me a kind of science that I have come to appreciate," he says. "We all know that science isn't just facts that you memorize. It's the discovery and surprise and learning from all the things that you don't know. Voyager has been such a great example of that."

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Kimm Fesenmaier
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Showing the Way to Improved Water-Splitting Catalysts

Caltech chemists identify the mechanism by which such catalysts work

PASADENA, Calif.—Scientists and engineers around the world are working to find a way to power the planet using solar-powered fuel cells. Such green systems would split water during daylight hours, generating hydrogen (H2) that could then be stored and used later to produce water and electricity. But robust catalysts are needed to drive the water-splitting reaction. Platinum catalysts are quite good at this, but platinum is too rare and expensive to scale up for use worldwide. Several cobalt and nickel catalysts have been suggested as cheaper alternatives, but there is still plenty of room for improvement. And no one has been able to determine definitively the mechanism by which the cobalt catalysts work, making it difficult to methodically design and construct improved catalysts.

Now chemists at the California Institute of Technology (Caltech) have determined the dominant mechanism for these cobalt catalysts. Their findings illuminate the road to the development of better catalysts—even suggesting a route to the development of catalysts based on iron, an element that is plentiful and cheap and could offer part of the answer to our energy woes.

"We've worked out this mechanism, and now we know what to do to make a really great catalyst out of something that's really cheap as dirt," says Harry Gray, the Arnold O. Beckman Professor of Chemistry at Caltech and senior author of a paper that describes the findings in the current issue of the Proceedings of the National Academy of Sciences (PNAS). "This work has completely changed our thinking about which catalyst designs to pursue."

A major barrier to improving the performance of man-made catalysts has been the lack of understanding of the mechanism—the chemical pathway that such catalysts follow leading to the production of hydrogen. As with any multistep manufacturing project, chemists need to know what is involved in each reaction that takes place—what goes in, what changes take place, and what comes out—in order to maximize efficiency and yield.

Three mechanisms have been suggested for how the cobalt catalysts help make hydrogen—one proposed by a French team, one developed by Caltech researchers, including Nate Lewis and Jonas Peters, and a third suggested more recently by a former graduate student in Gray's group, Jillian Dempsey (PhD '10). Until now, no one has managed to prove definitively which mechanisms actually occur or whether one was dominant, because the reactions proceed so quickly that it is difficult to identify the chemical intermediates that provide evidence of the reactions taking place. 

These cobalt catalysts are complexes that involve the metal bound to many different functional groups, or ligands. In the current study, Caltech postdoctoral scholar Smaranda Marinescu was able to add a set of ligands to cobalt, making the reaction slow down to the point where the researchers could actually observe the key intermediate using nuclear magnetic resonance (NMR) spectroscopy. "Once we could see that key intermediate by NMR and other methods, we were able to look at how it reacted in real time," Gray says. They saw that Dempsey's mechanism is the predominant pathway that these catalysts use to generate hydrogen. It involves a key reactive intermediate gaining an extra electron, forming a compound called cobalt(II)-hydride, which turns out to be the mechanism's active species.

In a previous PNAS paper, work by Gray and lead author Carolyn Valdez suggested that the Dempsey mechanism was the most likely explanation for the detected levels of activity. The new paper confirms that suggestion.

"We now know that you have to put another electron into cobalt catalysts in order to get hydrogen evolution," Gray says. "Now we have to start looking at designs with ligands that can accept that extra electron or those that can make atomic cobalt, which already has the extra electron."

Gray's group is now working on this latter approach. Moreover, these results give his group the information they need to develop an extremely active iron catalyst, and that will be their next big focus.

"We know now how to make a great catalyst," he says. "That's the bottom line."

In addition to Marinescu and Gray, Jay Winkler, a faculty associate and lecturer at Caltech, was also a coauthor on the paper, "Molecular mechanisms of cobalt-catalyzed hydrogen evolution." The work was supported by the National Science Foundation Center for Chemical Innovation in Solar Fuels as well as Chevron Phillips Chemical.

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Chemical Insights About Splitting Water
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Modeling the Genes for Development

Caltech biologists create the first predictive computational model of gene networks that control the development of sea-urchin embryos

PASADENA, Calif.—As an animal develops from an embryo, its cells take diverse paths, eventually forming different body parts—muscles, bones, heart. In order for each cell to know what to do during development, it follows a genetic blueprint, which consists of complex webs of interacting genes called gene regulatory networks.

Biologists at the California Institute of Technology (Caltech) have spent the last decade or so detailing how these gene networks control development in sea-urchin embryos. Now, for the first time, they have built a computational model of one of these networks.

This model, the scientists say, does a remarkably good job of calculating what these networks do to control the fates of different cells in the early stages of sea-urchin development—confirming that the interactions among a few dozen genes suffice to tell an embryo how to start the development of different body parts in their respective spatial locations. The model is also a powerful tool for understanding gene regulatory networks in a way not previously possible, allowing scientists to better study the genetic bases of both development and evolution.

"We have never had the opportunity to explore the significance of these networks before," says Eric Davidson, the Norman Chandler Professor of Cell Biology at Caltech. "The results are amazing to us."

The researchers described their computer model in a paper in the Proceedings of the National Academy of Sciences that appeared as an advance online publication on August 27.

The model encompasses the gene regulatory network that controls the first 30 hours of the development of endomesoderm cells, which eventually form the embryo's gut, skeleton, muscles, and immune system. This network—so far the most extensively analyzed developmental gene regulatory network of any animal organism—consists of about 50 regulatory genes that turn one another on and off.

To create the model, the researchers distilled everything they knew about the network into a series of logical statements that a computer could understand. "We translated all of our biological knowledge into very simple Boolean statements," explains Isabelle Peter, a senior research fellow and the first author of the paper. In other words, the researchers represented the network as a series of if-then statements that determine whether certain genes in different cells are on or off (i.e., if gene A is on, then genes B and C will turn off).

By computing the results of each sequence hour by hour, the model determines when and where in the embryo each gene is on and off. Comparing the computed results with experiments, the researchers found that the model reproduced the data almost exactly. "It works surprisingly well," Peter says.

Some details about the network may still be uncovered, the researchers say, but the fact that the model mirrors a real embryo so well shows that biologists have indeed identified almost all of the genes that are necessary to control these particular developmental processes. The model is accurate enough that the researchers can tweak specific parts—for example, suppress a particular gene—and get computed results that match those of previous experiments.

Allowing biologists to do these kinds of virtual experiments is precisely how computer models can be powerful tools, Peter says. Gene regulatory networks are so complex that it is almost impossible for a person to fully understand the role of each gene without the help of a computational model, which can reveal how the networks function in unprecedented detail.

Studying gene regulatory networks with models may also offer new insights into the evolutionary origins of species. By comparing the gene regulatory networks of different species, biologists can probe how they branched off from common ancestors at the genetic level.

So far, the researchers have only modeled one gene regulatory network, but their goal is to model the networks responsible for every part of a sea-urchin embryo, to build a model that covers not just the first 30 hours of a sea urchin's life but its entire embryonic development. Now that this modeling approach has been proven effective, Davidson says, creating a complete model is just a matter of time, effort, and resources. 

The title of the PNAS paper is "Predictive computation of genomic logic processing functions in embryonic development." In addition to Peter and Davidson, the other author on the PNAS paper is Emmanuel Faure, a former Caltech postdoctoral scholar who is now at the École Polytechnique in France. This work was supported by the National Institute of Child Health and Human Development and the National Institute of General Medical Sciences.

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Weighing Molecules One at a Time

Caltech-led physicists create first-ever mechanical device that measures the mass of a single molecule

PASADENA, Calif.—A team led by scientists at the California Institute of Technology (Caltech) has made the first-ever mechanical device that can measure the mass of individual molecules one at a time.

This new technology, the researchers say, will eventually help doctors diagnose diseases, enable biologists to study viruses and probe the molecular machinery of cells, and even allow scientists to better measure nanoparticles and air pollution.

The team includes researchers from the Kavli Nanoscience Institute at Caltech and Commissariat à l'Energie Atomique et aux Energies Alternatives, Laboratoire d'électronique des technologies de l'information (CEA-LETI) in Grenoble, France. A description of this technology, which includes nanodevices prototyped in CEA-LETI's facilities, appears in the online version of the journal Nature Nanotechnology on August 26.

The device—which is only a couple millionths of a meter in size—consists of a tiny, vibrating bridge-like structure. When a particle or molecule lands on the bridge, its mass changes the oscillating frequency in a way that reveals how much the particle weighs.

"As each particle comes in, we can measure its mass," says Michael Roukes, the Robert M. Abbey Professor of Physics, Applied Physics, and Bioengineering at Caltech. "Nobody's ever done this before."

The new instrument is based on a technique Roukes and his colleagues developed over the last 12 years. In work published in 2009, they showed that a bridge-like device—called a nanoelectromechanical system (NEMS) resonator—could indeed measure the masses of individual particles, which were sprayed onto the apparatus. The difficulty, however, was that the measured shifts in frequencies depended not only on the particle's actual mass, but also on where the particle landed. Without knowing the particle's landing site, the researchers had to analyze measurements of about 500 identical particles in order to pinpoint its mass.

But with the new and improved technique, the scientists need only one particle to make a measurement. "The critical advance that we've made in this current work is that it now allows us to weigh molecules—one by one—as they come in," Roukes says.

To do so, the researchers analyzed how a particle shifts the bridge's vibrating frequency. All oscillatory motion is composed of so-called vibrational modes. If the bridge just shook in the first mode, it would sway side to side, with the center of the structure moving the most. The second vibrational mode is at a higher frequency, in which half of the bridge moves sideways in one direction as the other half goes in the opposite direction, forming an oscillating S-shaped wave that spans the length of the bridge. There is a third mode, a fourth mode, and so on. Whenever the bridge oscillates, its motion can be described as a mixture of these vibrational modes.

The team found that by looking at how the first two modes change frequencies when a particle lands, they could determine the particle's mass and position, explains Mehmet Selim Hanay, a postdoctoral researcher in Roukes's lab and first author of the paper. "With each measurement we can determine the mass of the particle, which wasn't possible in mechanical structures before."

Traditionally, molecules are weighed using a method called mass spectroscopy, in which tens of millions of molecules are ionized—so that they attain an electrical charge—and then interact with an electromagnetic field. By analyzing this interaction, scientists can deduce the mass of the molecules.

The problem with this method is that it does not work well for more massive particles—like proteins or viruses—which have a harder time gaining an electrical charge. As a result, their interactions with electromagnetic fields are too weak for the instrument to make sufficiently accurate measurements.

The new device, on the other hand, does work well for large particles. In fact, the researchers say, it can be integrated with existing commercial instruments to expand their capabilities, allowing them to measure a wider range of masses.

The researchers demonstrated how their new tool works by weighing a molecule called immunoglobulin M (IgM), an antibody produced by immune cells in the blood. By weighing each molecule—which can take on different structures with different masses in the body—the researchers were able to count and identify the various types of IgM. Not only was this the first time a biological molecule was weighed using a nanomechanical device, but the demonstration also served as a direct step toward biomedical applications. Future instruments could be used to monitor a patient's immune system or even diagnose immunological diseases. For example, a certain ratio of IgM molecules is a signature of a type of cancer called Waldenström macroglobulinemia. 

In the more distant future, the new instrument could give biologists a view into the molecular machinery of a cell. Proteins drive nearly all of a cell's functions, and their specific tasks depend on what sort of molecular structures attach to them—thereby adding more heft to the protein—during a process called posttranslational modification. By weighing each protein in a cell at various times, biologists would now be able to get a detailed snapshot of what each protein is doing at that particular moment in time.

Another advantage of the new device is that it is made using standard, semiconductor fabrication techniques, making it easy to mass-produce. That's crucial, since instruments that are efficient enough for doctors or biologists to use will need arrays of hundreds to tens of thousands of these bridges working in parallel. "With the incorporation of the devices that are made by techniques for large-scale integration, we're well on our way to creating such instruments," Roukes says. This new technology, the researchers say, will enable the development of a new generation of mass-spectrometry instruments.

"This result demonstrates how the Alliance for Nanosystems VLSI, initiated in 2006, creates a favorable environment to carry out innovative experiments with state-of-the-art, mass-produced devices," says Laurent Malier, the director of CEA-LETI. The Alliance for Nanosystems VLSI is the name of the partnership between Caltech's Kavli Nanoscience Institute and CEA-LETI. "These devices," he says,"will enable commercial applications, thanks to cost advantage and process repeatability."

In addition to Roukes and Hanay, the other researchers on the Nature Nanotechnology paper, "Single-protein nanomechanical mass spectrometry in real time," are Caltech graduate students Scott Kelber and Caryn Bullard; former Caltech research physicist Akshay Naik (now at the Centre for Nano Science and Engineering in India); Caltech research engineer Derrick Chi; and Sébastien Hentz, Eric Colinet, and Laurent Duraffourg of CEA-LETI's Micro and Nanotechnologies innovation campus (MINATEC). Support for this work was provided by the Kavli Nanoscience Institute at Caltech, the National Institutes of Health, the National Science Foundation, the Fondation pour la Recherche et l'Enseignement Superieur from the Institut Merieux, the Partnership University Fund of the French Embassy to the U.S.A., an NIH Director's Pioneer Award, the Agence Nationale pour la Recherche through the Carnot funding scheme, a Chaire d'Excellence from Fondation Nanosciences, and European Union CEA Eurotalent Fellowships.  

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