Caltech Modeling Feat Sheds Light on Protein Channel's Function

PASADENA, Calif.—Chemists at the California Institute of Technology (Caltech) have managed, for the first time, to simulate the biological function of a channel called the Sec translocon, which allows specific proteins to pass through membranes. The feat required bridging timescales from the realm of nanoseconds all the way up to full minutes, exceeding the scope of earlier simulation efforts by more than six orders of magnitude. The result is a detailed molecular understanding of how the translocon works.

Modeling behavior across very different timescales is a major challenge in modern simulation research. "Computer simulations often provide almost uselessly detailed information on a timescale that is way too short, from which you get a cartoon, or something that might raise as many questions as it answers," says Thomas Miller, an assistant professor of chemistry at Caltech. "We've managed to go significantly beyond that, to create a tool that can actually be compared against experiments and even push experiments—to predict things that they haven't been able to see."

The new computational model and the findings based on its results are described by Miller and graduate student Bin Zhang in the current issue of the journal Cell Reports.

The Sec translocon is a channel in cellular membranes involved in the targeting and delivery of newly made proteins. Such channels are needed because the proteins that are synthesized at ribosomes must travel to other regions of the cell or outside the cell in order to perform their functions; however, the cellular membranes prevent even the smallest of molecules, including water, from passing through them willy-nilly. In many ways, channels such as the Sec translocon serve as gatekeepers—once the Sec translocon determines that a given protein should be allowed to pass through, it opens up and allows the protein to do one of two things: to be integrated into the membrane, or to be secreted completely out of the cell.

Scientists have disagreed about how the fate of a given protein entering the translocon is determined. Based on experimental evidence, some have argued that a protein's amino-acid sequence is what matters—that is, how many of its amino acids interact favorably with water and how many clash. This argument treats the process as one in equilibrium, where the extremely slow rate at which a ribosome adds proteins to the channel can be considered infinitely slow.  Other researchers have shown that slowing down the rate of protein insertion into the channel actually changes the outcome, suggesting that kinetic effects can also play a role.

"There was this equilibrium picture, suggesting that only the protein sequence is really important. And then there was an alternative picture, suggesting that kinetic effects are critical to understanding the translocon," Miller says. "So we wondered, could both pictures, in some sense, be right? And that turns out to be the case."

In 2010 and earlier this year, Miller and Zhang published papers in the Proceedings of the National Academy of Sciences and the Journal of the American Chemical Society describing atomistic simulations of the Sec translocon. These computer simulations attempt to account for every motion of every single atom in a system—and typically require so much computing time that they can only model millionths of seconds of activity, at most. Meanwhile, actual biological processes involving proteins in the translocon last many seconds or minutes.

Miller and Zhang were able to use their atomistic simulations to determine which parts of the translocon are most important and to calculate how much energy it costs those parts to move in ways that allow proteins to pass through. In this way, they were able to build a simpler version of the simulation that modeled important groupings of atoms, rather than each individual atom. Using the simplified simulation, they could simulate the translocon's activity over the course of more than a minute.

The researchers ran that simplified model tens of thousands of times and observed the different ways in which proteins move through the channel. In the simulation, any number of variables could be changed—including the protein's amino-acid sequence, its electronic charge, the rate at which it is inserted into the translocon, the length of its tail, and more. The effect of these alterations on the protein's fate was then studied, revealing that proteins move so slowly within the tightly confined environment of the translocon that the pace at which they are added to the channel during translation—a process that might seem infinitely slow—can become important. At the same time, Miller and Zhang saw that other relatively fast processes give rise to the results associated with the equilibrium behavior.

"In fact, both equilibrium and kinetically controlled processes are happening—but in a way that was not obvious until we could actually see everything working together," Miller says.

Beyond elucidating how the translocon works and reconciling seemingly disparate experimental results, the new simulation also lets the researchers perform experiments computationally that have yet to be tried in the lab. For example, they have run simulations with longer proteins and observed that at such lengths—unlike what has been seen with shorter proteins—the equilibrium picture begins to be affected by kinetic effects.  "This could bring the two experimental camps together, and to have led that would be kind of exciting," Miller says.

The new Cell Reports paper is titled "Long-timescale dynamics and regulation of Sec-facilitated protein translocation." The work was supported by the U.S. Office of Naval Research and the Alfred P. Sloan Foundation, with computational resources provided by the U.S. Department of Energy, the National Science Foundation, and the National Institute of General Medical Sciences.

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Kimm Fesenmaier
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Developing the Next Generation of Microsensors

Caltech researchers engineer microscale optical accelerometer

PASADENA, Calif.—Imagine navigating through a grocery store with your cell phone. As you turn down the bread aisle, ads and coupons for hot dog buns and English muffins pop up on your screen. The electronics industry would like to make such personal navigators a reality, but, to do so, they need the next generation of microsensors.

Thanks to an ultrasensitive accelerometer—a type of motion detector—developed by researchers at the California Institute of Technology (Caltech) and the University of Rochester, this new class of microsensors is a step closer to reality. Beyond consumer electronics, such sensors could help with oil and gas exploration deep within the earth, could improve the stabilization systems of fighter jets, and could even be used in some biomedical applications where more traditional sensors cannot operate.

Caltech professor of applied physics Oskar Painter and his team describe the new device and its capabilities in an advance online publication of the journal Nature Photonics.

Rather than using an electrical circuit to gauge movements, their accelerometer uses laser light. And despite the device's tiny size, it is an extremely sensitive probe of motion. Thanks to its low mass, it can also operate at a large range of frequencies, meaning that it is sensitive to motions that occur in tens of microseconds, thousands of times faster than the motions that the most sensitive sensors used today can detect.

"The new engineered structures we made show that optical sensors of very high performance are possible, and one can miniaturize them and integrate them so that they could one day be commercialized," says Painter, who is also codirector of Caltech's Kavli Nanoscience Institute.

Although the average person may not notice them, microchip accelerometers are quite common in our daily lives. They are used in vehicle airbag deployment systems, in navigation systems, and in conjunction with other types of sensors in cameras and cell phones. They have successfully moved into commercial use because they can be made very small and at low cost.

Accelerometers work by using a sensitive displacement detector to measure the motion of a flexibly mounted mass, called a proof mass. Most commonly, that detector is an electrical circuit. But because laser light is one of the most sensitive ways to measure position, there has been interest in making such a device with an optical readout. For example, projects such as the Laser Interferometer Gravitational-Wave Observatory (LIGO) rely on optical interferometers, which use laser light reflecting off mirrors separated by kilometers of distance to sensitively measure relative motion of the end mirrors. Lasers can have very little intrinsic noise—meaning that their intensity fluctuates little—and are typically limited by the quantum properties of light itself, so they make it much easier to detect very small movements.

People have tried, with limited success, to make miniature versions of these large-scale interferometers. One stumbling block for miniaturization has been that, in general, the larger the proof mass, the larger the resulting motion when the sensor is accelerated. So it is typically easier to detect accelerations with larger sensors. Also, when dealing with light rather than electrons—as in optical accelerometers—it is a challenge to integrate all the components (the lasers, detectors, and interferometer) into a micropackage.

"What our work really shows is that we can take a silicon microchip and scale this concept of a large-scale optical interferometer all the way down to the nanoscale," Painter says. "The key is this little optical cavity we engineered to read out the motion."

The optical cavity is only about 20 microns (millionths of a meter) long, a single micron wide, and a few tenths of a micron thick. It consists of two silicon nanobeams, situated like the two sides of a zipper, with one side attached to the proof mass. When laser light enters the system, the nanobeams act like a "light pipe," guiding the light into an area where it bounces back and forth between holes in the nanobeams. When the tethered proof mass moves, it changes the gap between the two nanobeams, resulting in a change in the intensity of the laser light being reflected out of the system. The reflected laser signal is in fact tremendously sensitive to the motion of the proof mass, with displacements as small as a few femtometers (roughly the diameter of a proton) being probed on the timescale of a second.

It turns out that because the cavity and proof mass are so small, the light bouncing back and forth in the system pushes the proof mass—and in a special way: when the proof mass moves away, the light helps push it further, and when the proof mass moves closer, the light pulls it in. In short, the laser light softens and damps the proof mass's motion.

"Most sensors are completely limited by thermal noise, or mechanical vibrations—they jiggle around at room temperature, and applied accelerations get lost in that noise," Painter says. "In our device, the light applies a force that tends to reduce the thermal motion, cooling the system." This cooling—down to a temperature of three kelvins (about –270°C) in the current devices—increases the range of accelerations that the device can measure, making it capable of measuring both extremely small and extremely large accelerations.

"We made a very sensitive sensor that, at the same time, can also measure very large accelerations, which is valuable in many applications," Painter says.

The team envisions its optical accelerometers becoming integrated with lasers and detectors in silicon microchips. Microelectronics companies have been working for the past 10 or 15 years to try to integrate lasers and optics into their silicon microelectronics. Painter says that a lot of engineering work still needs to be done to make this happen, but adds that "because of the technological advancements that have been made by these companies, it looks like one can actually start making microversions of these very sensitive optical interferometers."

"Professor Painter's research in this area nicely illustrates how the Engineering and Applied Science faculty at Caltech are working at the edges of fundamental science to invent the technologies of the future," says Ares Rosakis, chair of Caltech's Division of Engineering and Applied Science.  "It is very exciting to envision the ways this research might transform the microelectronics industry and our daily lives."

The lead authors on the paper, titled "A high-resolution microchip optomechanical accelerometer," have all worked in Painter's lab. Alexander Krause and Tim Blasius are currently graduate students at Caltech, while Martin Winger is a former postdoctoral scholar who now works for a sensor company called Sensirion in Zurich, Switzerland. This work was performed in collaboration with Qiang Lin, a former postdoctoral scholar of the Painter group, who now leads his own research group at the University of Rochester. The work is supported by the Defense Advanced Research Projects Administration QuASaR program, the National Science Foundation Graduate Research Fellowship Program, and Intellectual Ventures.

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Kimm Fesenmaier
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How I Spent My Summer Vacation

A SURF Video Diary

Last summer, Caltech junior Julie Jester worked on a project that might one day partially counteract blindness caused by a deteriorating retina. Her job: to help Assistant Professor of Electrical Engineering Azita Emami and her graduate students create the communications link between a tiny camera and a novel wireless neural stimulator that can be surgically inserted into the eye.

Now in its 34th year, Caltech's Summer Undergraduate Research Fellowships (SURF) program has paired nearly 7,000 students with real-world, hands-on projects in the labs of Caltech faculty and JPL staff.

 

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Doug Smith
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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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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."

Writer: 
Kimm Fesenmaier
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