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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Marcus Woo
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Learning One of Cancer's Tricks

Caltech chemists determine one way tumors meet their growing needs

PASADENA, Calif.— Behaving something like ravenous monsters, tumors need plentiful supplies of cellular building blocks such as amino acids and nucleotides in order to keep growing at a rapid pace and survive under harsh conditions. How such tumors meet these burgeoning demands has not been fully understood. Now chemists at the California Institute of Technology (Caltech) have shown for the first time that a specific sugar, known as GlcNAc ("glick-nack"), plays a key role in keeping the cancerous monsters "fed." The finding suggests new potential targets for therapeutic intervention.

The new results appear in this week's issue of the journal Science

The research team—led by Linda Hsieh-Wilson, professor of chemistry at Caltech—found that tumor cells alter glycosylation, the addition of carbohydrates (in this case GlcNAc) to their proteins, in response to their surroundings. This ultimately helps the cancerous cells survive. When the scientists blocked the addition of GlcNAc to a particular protein in mice, tumor-cell growth was impaired.

The researchers used chemical tools and molecular modeling techniques developed in their laboratory to determine that GlcNAc inhibits a step in glycolysis (not to be confused with glycosylation), a metabolic pathway that involves 10 enzyme-driven steps. In normal cells, glycolysis is a central process that produces high-energy compounds that the cell needs to do work. But Hsieh-Wilson's team found that when GlcNAc attaches to the enzyme phosphofructokinase 1 (PFK1), it suppresses glycolysis at an early phase and reroutes the products of previous steps into a different pathway—one that yields the nucleotides a tumor needs to grow, as well as molecules that protect tumor cells. So GlcNAc causes tumor cells to make a trade—they produce fewer high-energy compounds in order to get the products they need to grow and survive.

"We have identified a novel molecular mechanism that cancer cells have co-opted in order to produce intermediates that allow them to grow more rapidly and to help them combat oxidative stress," says Hsieh-Wilson, who is also an investigator with the Howard Hughes Medical Institute.

This is not the first time scientists have identified a mechanism by which tumor cells might produce the intermediates they need to survive. But most other mechanisms have involved genetic alterations, or mutations—permanent changes that lead to less active forms of enzymes, for example. "What's unique here is that the addition of GlcNAc is dynamic and reversible," says Hsieh-Wilson. "This allows a cancer cell to more rapidly alter its metabolism depending on the environment that it encounters."

In their studies, Hsieh-Wilson's team found that this glycosylation—the addition of GlcNAc to PFK1—is enhanced under conditions associated with tumors, such as low oxygen levels.  They also found that glycosylation of PFK1 was sensitive to the availability of nutrients. If certain nutrients were absent, glycosylation was increased, and the tumor was able to compensate for the dearth of nutrients by changing the cell's metabolism.

When the researchers analyzed human breast and lung tumor tissues, they found GlcNAc-related glycosylation was elevated two- to fourfold in the majority of tumors relative to normal tissue from the same patients. Then, working with mice injected with human lung-cancer cells, the researchers replaced the existing PFK1 enzymes with either the normal PFK1 enzyme or a mutant form that could no longer be glycosylated. The mice with the mutant form of PFK1 showed decreased tumor growth, demonstrating that blocking glycosylation impairs cancerous growth.

The work suggests at least two possible avenues for future investigations into fighting cancer. One would be to develop compounds that prevent PFK1 from becoming glycosylated, similar to the mutant PFK1 enzymes in the present study. The other would be to activate PFK1 enzymes in order to keep glycolysis operating normally and help prevent cancer cells from altering their cellular metabolism in favor of cancerous growth.

Hsieh-Wilson's group has previously studied GlcNAc-related glycosylation in the brain. They have demonstrated, for example, that the addition of GlcNAc to a protein called CREB inhibits the protein's ability to turn on genes needed for long-term memory storage. On the other hand, they have also shown that having significantly lower levels of GlcNAc in the forebrain leads to neurodegeneration. "The current thinking is that there's a balance between too little and too much glycosylation," says Hsieh-Wilson. "Being at either extreme make things go awry, whether it's in the brain or in the case of cancer cells."

Additional Caltech coauthors on the paper, "Phosphofructokinase 1 Glycosylation Regulates Cell Growth and Metabolism," were lead author Wen Yi, a postdoctoral scholar in Hsieh-Wilson's group; Peter Clark, a former graduate student in Hsieh-Wilson's group; and William Goddard III, the Charles and Mary Ferkel Professor of Chemistry, Materials Science, and Applied Physics. Daniel Mason and Eric Peters of the Genomics Institute of the Novartis Research Foundation and Marie Keenan, Collin Hill, and Edward Driggers of Agios Pharmaceuticals were also coauthors.

The work was supported by the National Institutes of Health, the Department of Defense Breast Cancer Research Program, and a Tobacco-Related Disease Research Program postdoctoral fellowship.

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Kimm Fesenmaier
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Thinking and Choosing in the Brain

Caltech researchers study over 300 lesion patients

PASADENA, Calif.—The frontal lobes are the largest part of the human brain, and thought to be the part that expanded most during human evolution. Damage to the frontal lobes—which are located just behind and above the eyes—can result in profound impairments in higher-level reasoning and decision making. To find out more about what different parts of the frontal lobes do, neuroscientists at the California Institute of Technology (Caltech) recently teamed up with researchers at the world's largest registry of brain-lesion patients. By mapping the brain lesions of these patients, the team was able to show that reasoning and behavioral control are dependent on different regions of the frontal lobe than the areas called upon when making a decision.

Their findings are described online this week in the early edition of the Proceedings of the National Academy of Sciences (PNAS).

The team analyzed data that had been acquired over a 30-plus-year time span by scientists from the University of Iowa's department of neurology—which has the world's largest lesion patient registry. They used that data to map brain activity in nearly 350 people with damage, or lesions, in their frontal lobes. The records included data on the performances of each patient while doing certain cognitive tasks.

By examining these detailed files, the researchers were able to see exactly which parts of the frontal lobes are critical for tasks like behavioral control and decision making.  The intuitive difference between these two types of processing is something we encounter in our lives all the time. Behavioral control happens when you don't order an unhealthy chocolate sundae you desire and go running instead. Decision making based on reward, on the other hand, is more like trying to win the most money in Vegas—or indeed choosing the chocolate sundae.

"These are really unique data that could not have been obtained anywhere else in the world," explains Jan Glascher, lead author of the study and a visiting associate in psychology at Caltech. "To address the question that we were interested in, we needed both a large number of patients with very well-measured lesions in the brain, and also a very thorough assessment of their reasoning and decision-making abilities across a battery of tasks."

That quantification of the lesions as well as the different task measurements came from several decades of work led by two coauthors on the study: Hanna Damasio, Dana Dornsife Chair in Neuroscience at the University of Southern California (USC); and Daniel Tranel, professor or neurology and psychology at the University of Iowa.

"The patterns of lesions that impair specific tasks showed a very clear separation between those regions of the frontal lobes necessary for controlling behavior, and those necessary for how we give value to choices and how we make decisions," says Tranel.

Ralph Adolphs, Bren Professor of Psychology and Neuroscience at Caltech and a coauthor of the study, says that aspects of what the team found had been observed previously using fMRI methods in healthy people. But, he adds, those previous studies only showed which parts of the brain are activated when people think or choose, but not which are the most critical areas, and which are less important. 

"Only lesion mapping, like we did in the present study, can show you which parts of the brain are actually necessary for a particular task," he says. "This information is crucial, not only for basic cognitive neuroscience, but also for linking these findings to clinical relevance." 

For example, several different parts of the brain might be activated when you are making a particular type of decision, explains Adolphs. If there is a lesion in one of these areas, the rest of your brain might be able to compensate, leaving little or no impairment. But if a lesion occurs in another area, you might wind up with a lifelong disability in decision making. Knowing which lesion leads to which outcome is something only this kind of detailed lesion study can provide, he says.

"That knowledge will be tremendously useful for prognosis after brain injury," says Adolphs. "Many people suffer injury to their frontal lobes—for instance, after a head injury during an automobile accident—but the precise pattern of the damage will determine their eventual impairment."

According to Tranel, the team is already working on their next project, which will use lesion mapping to look at how damage to particular brain regions can impact mood and personality. " There are so many other aspects of human behavior, cognition, and emotion to investigate here, that we've barely begun to scratch the surface," he says.

Other collaborators on the PNAS paper, "Lesion Mapping of Cognitive Control and Value-based Decision-making in the Prefrontal Cortex," were Lynn Paul, a senior research scientist at Caltech; David Rudrauf and Matt Calamia from the University of Iowa; and Antoine Bechara from USC. The study was supported by grants from the German Ministry of Research and Education, the National Institutes of Health, the Kiwanis Foundation, and the Gordon and Betty Moore Foundation.

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Katie Neith
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Keeping Up with Curiosity

When Curiosity touched down safely on Mars on August 5, John Grotzinger, the mission's chief scientist and the Fletcher Jones Professor of Geology at Caltech, was given the "keys" to the car-sized rover.

Since then, most of Curiosity's time has been taken up by a series of checkouts to make sure her instruments, antennae, and subsystems are working properly. But the rover has been able to take some scientific measurements of the radiation environment and of the temperature on Mars, for example. And she has relayed hundreds of images back to Earth, giving the science team plenty to study and discuss.

On Wednesday, August 8, the team shared two stitched-together full-resolution images taken by the rover's navigation camera. Part of the rover's deck is visible in the foreground, with its low-gain antenna clearly sticking up. In the distance, the rim of Gale Crater—the ancient impact crater in which Curiosity landed—appears almost like rippling mountains. 

Describing the image during a press conference, Grotzinger said the science team had been struck by how Earthlike the landscape appeared. "You would really be forgiven for thinking that NASA was trying to pull a fast one on you, and we actually put a rover out in the Mojave Desert and took a picture," he said, adding that it almost looked as though some Los Angeles smog was adding a haze.

The team had also zoomed in to take a closer look at a spot where the thrusters on the rover's descent stage had blown away the soil, revealing what Grotzinger said looked to be exposed bedrock. With such interesting nearby potential targets, Grotzinger said the core of the science team's discussions had been whether to begin using Curiosity's sampling tools and instruments right there or to first drive somewhere else once they have that capability.

On Thursday, the rover delivered its first full-color 360° panoramic image, which it captured using its mast camera. A JPL press release tells more about that image and the science team's recent activities.

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Kimm Fesenmaier
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Now On Mars: "A One-Ton, Automobile-Sized Piece of American Ingenuity"

The mood in von Karman Auditorium at the Jet Propulsion Laboratory (JPL) late Sunday night was overwhelmingly, almost deliriously, celebratory. The Mars Science Laboratory (MSL) rover, Curiosity, touched down safely on Mars at 10:32 p.m. PDT and minutes later relayed its first black-and-white thumbnail images back to Earth, showing one of its wheels firmly planted on Martian soil. During a postlanding press conference, a conga-line-type parade of team members wearing light-blue polo shirts streamed into and coiled around the auditorium, as each person high-fived the team managers at the front of the room. The entry, descent, and landing (EDL) team even started chanting, "E-D-L, E-D-L."

They had good reason to celebrate. Based on the first engineering data that has come back to Earth about the health and safety of the vehicle, the rover is operating according to plan after the harrowing EDL sequence, famously known as the "seven minutes of terror."

Curiosity is a car-sized analytical laboratory on six wheels. The rover carries 10 scientific instruments, 17 cameras, and a radioisotope thermoelectric generator that can keep it powered for years to come. Its goal? To explore its landing site—an impact basin formed more than 3 billion years ago, called Gale Crater—for evidence of environments that either once were or now are habitable. 

To get to this point, many people on the MSL team have worked eight or more years on the mission, in part trying to think of every potential problem Curiosity could encounter and then preparing the vehicle for such situations. But as landing night approached, the engineers and scientists of the mission had less and less control over the MSL spacecraft. And in the end, as much of the world sat on edge, waiting for a thumbs up or thumbs down from Curiosity, so too did the team.

Perhaps that's where the superstitions of landing day come in. In the mission control room at JPL on Sunday there were plenty of lucky peanuts to go around—a tradition that the team has indulged in for nearly 40 years, since the Ranger 7 mission. There was at least one "playoff beard," there were lucky trinkets in hand, and Bobak Ferdowsi, the activity lead and flight director of the mission, let the team vote on his lucky coiffure for the event. (They went with a red-and-blue mohawk hairdo with stars shaved into the sides.)

But, of course, much more than luck guided Curiosity to a safe landing. The team had tested and retested every aspect of the vehicle and practiced the sequence many times. In briefings leading up to landing night, they repeatedly told reporters that they were confident in the spacecraft's preparation, but there was always the caveat that landing on Mars is a risky business and many things could go wrong. As Adam Steltzner, the EDL phase lead at JPL put it on Sunday morning, "We're rationally confident, emotionally terrified."

As it turned out, everything went terrorlessly during the seven minutes. The Mars Odyssey orbiter flew over and established a good communication link with MSL as hoped, and the team was able to follow MSL's progress toward the surface of Mars, sky-crane maneuver and all. Several members of the team said the evening even took on a surreal feeling, as though the whole thing was just a movie.

"It just was magical—everything went so smoothly," said John Grotzinger, the chief scientist of the MSL mission and the Fletcher Jones Professor of Geology at Caltech, following the landing. "I had to just keep reminding myself it wasn't a test anymore."

If there was any remaining misgiving about the difficulty of the feat MSL had accomplished, President Obama's science advisor, John Holdren, erased it before a cheering auditorium, telling onlookers that the landing was, "by any measure, the most challenging mission ever attempted in the history of robotic planetary exploration." The applause grew even louder when he said, "If anybody has been harboring doubts about the status of U.S. leadership in space, well, there's a one-ton, automobile-sized piece of American ingenuity, and it's sitting on the surface of Mars right now."

JPL director Charles Elachi took the conversation back to the Olympics. (Sports metaphors were prevalent throughout the run-up to the landing, with comparisons to not only the Olympics but also to the Super Bowl and a marathon.) "This team came back with the gold," he said.

The first black-and-white images from the rover were themselves a prize for the engineers and scientists on the team, since they show an area of Mars no one has ever seen up close. They also provide evidence that the rover is alive and well on the surface of the red planet. And even though the very first images were low-resolution and taken with the hazard-avoidance cameras that still had their transparent dust covers on at the time, Grotzinger said of one image, "I think that is the best picture of Mars I've ever seen."

No one knows exactly what Curiosity will find when she (as with ships, it has become common to refer to the rover as a female) begins her geologic investigation in earnest. Scientists hope she might identify organic compounds, those carbon-containing molecules that are necessary for life as we know it. For now, Curiosity is going through a number of engineering checkouts, running her first scientific activities, and taking and relaying images of her landing site to help the team pinpoint her location and better understand her surroundings. The team expects that it may be a couple of weeks before the rover goes for a short drive in Gale Crater and longer still before she scoops up her first soil sample.

Curiosity's front left hazard-avoidance camera snapped this full-resolution photo, which features the rover's shadow, some dark sand dunes, and the three-mile-high Mount Sharp.
Credit: NASA/JPL-Caltech

When she does, based on everything that is known about the landing site, those samples should be scientifically interesting. The rover touched down in between an alluvial fan—a geologic feature where debris from the rim of the crater might have collected—and a three-mile-high mountain of layered rock. That mountain—informally named Mount Sharp in honor of the late Robert Sharp, a Caltech geologist and former chair of the then Division of Geological Sciences—is the mission's primary science target. The MSL team looks at Mount Sharp the way American geologist John Wesley Powell might have seen the Grand Canyon more than 140 years ago—as an exposed record of the planet's history, preserved in rock form. That gives Curiosity an elegantly simple exploration model. As Grotzinger likes to say, "We'll just start at the bottom of the mountain, interrogate the layers and make the measurements, and see what the planet's trying to tell us."

The MSL mission is also seen as a necessary precursor to any future manned missions to Mars. It has already shown that it is possible to deliver a metric ton of equipment to the surface of the red planet, and has measured the radiation environment experienced inside the spacecraft on the way there. As NASA administrator Charles Bolden said after landing, "Today, right now, the wheels of Curiosity have begun to blaze a trail for human footprints on Mars."

The Mars Science Laboratory mission is managed by JPL for NASA's Science Mission Directorate in Washington. Curiosity was designed, developed, and assembled at JPL, a division of Caltech.

Follow the mission on Facebook and on Twitter at http://www.facebook.com/marscuriosity and http://www.twitter.com/marscuriosity.

For information about the mission, visit http://mars.jpl.nasa.gov/msl/.

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Kimm Fesenmaier
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A Tale of Curiosity's Landing Night
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Home Sweet Mars

NASA's Mars Science Laboratory successfully lands on the red planet

The "seven minutes of terror" are over, and members of NASA's Mars Science Laboratory (MSL) team have finally let out a collective sigh of relief.

The newest Mars rover, Curiosity, touched down successfully on the red planet on Sunday night and is now parked, as planned, near the base of a scientifically tantalizing layered mountain within Gale Crater, just south of the Martian equator.

"Touchdown confirmed," said Allen Chen, MSL's operations lead for entry, descent, and landing, at 10:32 p.m. PDT from mission control at the Jet Propulsion Laboratory. Then the engineers and scientists in the room—who had been intently focused on their computer screens just moments before—started clapping and high-fiving each other, some even crying tears of joy. The celebrations continued as each of three low-resolution images taken by the rover's hazard-avoidance cameras appeared on screen, showing one of Curiosity's wheels and the vehicle's shadow on Mars.

Caltech president Jean-Lou Chameau joined in the festivities. "This is a win for humankind—Curiosity belongs to everyone," said Chameau. "Exploring Mars will help us develop a greater understanding of the universe and our place in it. This extraordinary accomplishment is testament to the talent and hard work of the many dedicated scientists and engineers at JPL and Caltech."

In the days ahead, Curiosity will begin an analysis of its instruments and subsystems, take photographs of its surroundings, and begin using some of its 10 scientific instruments. The team expects that it will be at least a week before the rover goes for its first spin on Mars.

Having traveled about 354 million miles, MSL has cleared some major hurdles, but the scientific journey is just beginning. 

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Kimm Fesenmaier
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Countdown to Mars: Some Curious Facts

Since launching in November 2011, NASA's Mars Science Laboratory (MSL) has been traveling full steam ahead on a journey that will traverse over 350 million miles, ending on the Red Planet at 10:31 p.m. on Sunday, August 5. Tucked into a spacecraft for safekeeping during flight, MSL contains a rover named Curiosity. As part of a long-term effort of robotic exploration, the rover's mission is to determine the planet's habitability. If everything goes as planned, Curiosity—which was designed, built, and tested at JPL—will become the fourth rover to survey Mars.

Here are some more facts about Curiosity and the mission:

The estimated length of time it will take the rover to make its entry, descent, and landing on Mars once it arrives at the Red Planet's atmosphere: About seven minutes. Dubbed the "seven minutes of terror" by NASA, MSL will employ a parachute, landing rockets, a hovering sky crane, and other complicated mechanisms to help lower the rover to the surface of Mars.

The diameter of the parachute that will assist in Curiosity's landing: 51 feet. Made from white and orange material, the parachute will bring Caltech colors to the Red Planet.

Landing site: The rover will land near the base of Mount Sharp, inside Gale Crater. Mount Sharp, a layered mountain that rises three miles above the crater floor, was named to honor the late Caltech geologist Bob Sharp (BS '34, MS '35).

The number of possible landing sites scientists considered before deciding on Gale Crater: 60. Gale Crater was chosen because it is thought to contain elements that are important to the search for the ingredients of life.

Weather on Mars: Cold and windy with wind gusts of up to 90 mph—as strong as some hurricane winds on Earth. Mars is home to dust storms and quickly moving whirlwinds known as dust devils. Temperatures on the planet can get as cold as minus 199 degrees Fahrenheit.

Curiosity's mass: 1,982 pounds. The rover has a mass close to that of a MINI Cooper, but it is more like a small SUV in size.

Speed of Curiosity: On average, the rover is expected to travel across the surface of Mars at about 30 meters (98 feet) per hour, based on power levels, slippage, steepness of the terrain, visibility, and other variables.

The number of cameras on Curiosity: 17. The rover also has 10 scientific instruments (some of which are part of the group of 17 cameras) to do many of the tasks scientists do in a lab. Instead of sending samples back to Earth for humans to analyze, the Curiosity rover will thus be able to do laboratory tests right from the Martian surface.

Length of Curiosity's robotic arm: Seven feet. The arm is capable of collecting powdered samples from rocks, scooping soil, preparing and delivering samples for analytic instruments, and brushing surfaces on the planet.

Time on Mars: The plan is for Curiosity to operate on the surface of Mars for one Martian year. A Martian year is equal to 98 weeks, or 687 days, on Earth.

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Katie Neith
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Mission to Mars

After journeying more than 340 million miles over the course of eight months, NASA's Mars Science Laboratory (MSL)—the most capable robotic mission ever sent to the Red Planet—is quickly approaching its destination. The spacecraft is scheduled to touch down on the evening of August 5. If all goes smoothly, mission control at the Jet Propulsion Laboratory (JPL) will receive confirmation of the rover's landing at around 10:31 p.m. (PDT).  

After an action-packed entry, descent, and landing, the car-sized rover, named Curiosity, will be poised on all six wheels inside Gale Crater, an ancient impact crater just south of the Martian equator. Roughly the size of the Los Angeles Basin—at 154 kilometers (96 miles) in diameter—the crater was selected in large part because it holds a five-kilometer (three-mile) high mountain, dubbed Mount Sharp in honor of the late Robert P. Sharp, the venerated former chair of Caltech's then Division of Geological Sciences. The MSL team hopes to use Curiosity and its suite of 10 scientific instruments to read the history of Mars in Mount Sharp's layered rock. Their mission is to search for evidence of a Martian environment that could have once supported microbial life.

"We don't know what the story is going to be at Gale Crater, but we've got a wonderfully simple exploration model," says John Grotzinger, Caltech's Fletcher Jones Professor of Geology and the chief scientist on the project. "We'll just start at the bottom of the mountain, interrogate the layers and make the measurements, and see what the planet's trying to tell us. I don't think we can lose."

A feature-length story about this Mission to Mars appears in the Summer 2012 issue of E&S magazine.  

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Kimm Fesenmaier
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Medusa Reimagined

Caltech-led team reverse engineers a jellyfish with the ability to swim

PASADENA, Calif.—When one observes a colorful jellyfish pulsating through the ocean, Greek mythology probably doesn't immediately come to mind. But the animal once was known as the medusa, after the snake-haired mythological creature its tentacles resemble. The mythological Medusa's gaze turned people into stone, and now, thanks to recent advances in bio-inspired engineering, a team led by researchers at the California Institute of Technology (Caltech) and Harvard University have flipped that fable on its head: turning a solid element—silicon—and muscle cells into a freely swimming "jellyfish."

Their method for building the tissue-engineered jellyfish, dubbed Medusoid, is outlined in a Nature Biotechnology paper that appears as an advance online publication on July 22. 

"A big goal of our study was to advance tissue engineering," says Janna Nawroth, a doctoral student in biology at Caltech and lead author of the study. "In many ways, it is still a very qualitative art, with people trying to copy a tissue or organ just based on what they think is important or what they see as the major components—without necessarily understanding if those components are relevant to the desired function or without analyzing first how different materials could be used." Because a particular function—swimming, say—doesn't necessarily emerge just from copying every single element of a swimming organism into a design, "our idea," she says, "was that we would make jellyfish functions—swimming and creating feeding currents—as our target and then build a structure based on that information."

Jellyfish are believed to be the oldest multi-organ animals in the world, possibly existing on Earth for the past 500 million years. Because they use a muscle to pump their way through the water, their function—on a very basic level—is similar to that of a human heart, which makes the animal a good biological system to analyze for use in tissue engineering.

"It occurred to me in 2007 that we might have failed to understand the fundamental laws of muscular pumps," says Kevin Kit Parker, Tarr Family Professor of Bioengineering and Applied Physics at Harvard and a coauthor of the study. "I started looking at marine organisms that pump to survive. Then I saw a jellyfish at the New England Aquarium, and I immediately noted both similarities and differences between how the jellyfish pumps and the human heart. The similarities help reveal what you need to do to design a bio-inspired pump."

Parker contacted John Dabiri, professor of aeronautics and bioengineering at Caltech—and Nawroth's advisor—and a partnership was born. Together, the two groups worked for years to understand the key factors that contribute to jellyfish propulsion, including the arrangement of their muscles, how their bodies contract and recoil, and how fluid-dynamic effects help or hinder their movements. Once these functions were well understood, the researchers began to design the artificial jellyfish.    

Nawroth and colleagues looked at several materials from which to fashion the body of their beast, eventually settling on an elastic material that is relatively similar to the "jelly" found in a real jellyfish. The team at Harvard—with the help of Nawroth, who spent time on both campuses during the length of the project—fashioned the silicone polymer that makes up the body of the Medusoid into a thin membrane that resembles a small jellyfish, with eight arm-like appendages. Next, they printed a pattern made of protein onto the membrane that resembled the muscle architecture in the real animal. The protein pattern serves as a road map for growth and organization of dissociated rat tissue—individual heart muscle cells that retain the ability to contract—into a coherent swimming muscle.

When the researchers set their creation free in an electrically conducting container of fluid and oscillated the voltage from zero volts to five, they shocked the Medusoid into swimming with synchronized contractions that mimic those of real jellyfish. In fact, the muscle cells started to contract a bit on their own even before the electrical current was applied.

"I was surprised that with relatively few components—a silicone base and cells that we arranged—we were able to reproduce some pretty complex swimming and feeding behaviors that you see in biological jellyfish," says Dabiri, with fluid-dynamics measurements that match up to those of the real animal. "I'm pleasantly surprised at how close we are getting to matching the natural biological performance, but also that we're seeing ways in which we can probably improve on that natural performance. The process of evolution missed a lot of good solutions."

This advance in bio-inspired engineering, the team says, demonstrates that it is inadequate to simply mimic nature: the focus must be on function. Their design strategy, they say, will be broadly applicable to the reverse engineering of muscular organs in humans. In addition, Dabiri and colleagues say, their new process of harvesting heart-muscle cells from one organism and reorganizing them in an artificial system will be useful in building an engineered system using biological materials.

"As engineers, we are very comfortable with building things out of steel, copper, concrete," says Parker. "I think of cells as another kind of building substrate, but we need rigorous quantitative design specs to move tissue engineering from arts and crafts to a reproducible type of engineering. The jellyfish provides a design algorithm for reverse engineering an organ's function and developing quantitative design and performance specifications. We can complete the full exercise of the engineer's design process: design, build, and test."

The team's next goal is to design a completely self-contained system that is able to sense and actuate on its own using internal signals, as human hearts do. Nawroth and Dabiri would also like for the Medusoid to be able to go out and gather food on its own. Then, researchers could think about systems that could live in the human body for years at a time without having to worry about batteries because the system would be able to fend for itself. For example, these systems could be the basis for a pacemaker made with biological elements.

"We're reimagining how much we can do in terms of synthetic biology," says Dabiri. "A lot of work these days is done to engineer molecules, but there is much less effort to engineer organisms. I think this is a good glimpse into the future of re-engineering entire organisms for the purposes of advancing biomedical technology. We may also be able to engineer applications where these biological systems give us the opportunity to do things more efficiently, with less energy usage."

Other Harvard collaborators who contributed to the Nature Biotechnology paper, "A Tissue-Engineered Jellyfish with Biomimetic Propulsion," are Hyungsuk Lee, Adam W. Feinberg, Crystal M. Ripplinger, Megan L. McCain, and Anna Grosberg, who earned her PhD in bioengineering at Caltech. Funding for the study included grants from the Wyss Institute for Biologically Inspired Engineering at Harvard, the National Science Foundation (NSF), the National Institutes of Health, the Office of Naval Research, and NSF Program in Fluid Dynamics.

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Katie Neith
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Caltech-led Team Reverse Engineers a Jellyfish
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An Earthquake in a Maze

Caltech researchers provide highest-resolution observations yet of the complex 2012 Sumatra earthquake

PASADENA, Calif.—The powerful magnitude-8.6 earthquake that shook Sumatra on April 11, 2012, was a seismic standout for many reasons, not the least of which is that it was larger than scientists thought an earthquake of its type—an intraplate strike-slip quake—could ever be. Now, as Caltech researchers report on their findings from the first high-resolution observations of the underwater temblor, they point out that the earthquake was also unusually complex—rupturing along multiple faults that lie at nearly right angles to one another, as though racing through a maze.

The new details provide fresh insights into the possibility of ruptures involving multiple faults occurring elsewhere—something that could be important for earthquake-hazard assessment along California's San Andreas fault, which itself is made up of many different segments and is intersected by a number of other faults at right angles.

"Our results indicate that the earthquake rupture followed an exceptionally tortuous path, breaking multiple segments of a previously unrecognized network of perpendicular faults," says Jean-Paul Ampuero, an assistant professor of seismology at Caltech and one of the authors of the report, which appears online today in Science Express. "This earthquake provided a rare opportunity to investigate the physics of such extreme events and to probe the mechanical properties of Earth's materials deep beneath the oceans."

Most mega-earthquakes occur at the boundaries between tectonic plates, as one plate sinks beneath another. The 2012 Sumatra earthquake is the largest earthquake ever documented that occurred away from such a boundary—a so-called intraplate quake. It is also the largest that has taken place on a strike-slip fault—the type of fault where the land on either side is pushing horizontally past the other.

The earthquake happened far offshore, beneath the Indian Ocean, where there are no geophysical monitoring sensors in place. Therefore, the researchers used ground-motion recordings gathered by networks of sensors in Europe and Japan, and an advanced source-imaging technique developed in Caltech's Seismological Laboratory as well as the Tectonics Observatory to piece together a picture of the earthquake's rupture process. 

Lingsen Meng, the paper's lead author and a graduate student in Ampuero's group, explains that technique by comparing it with how, when standing in a room with your eyes closed, you can often still sense when someone speaking is walking across the room. "That's because your ears measure the delays between arriving sounds," Meng says. "Our technique uses a similar idea. We measure the delays between different seismic sensors that are recording the seismic movements at set locations." Researchers can then use that information to determine the location of a rupture at different times during an earthquake. Recent developments of the method are akin to tracking multiple moving speakers in a cocktail party.

Using this technique, the researchers determined that the three-minute-long Sumatra earthquake involved at least three different fault planes, with a rupture propagating in both directions, jumping to a perpendicular fault plane, and then branching to another.

"Based on our previous understanding, you wouldn't predict that the rupture would take these bends, which were almost right angles," says Victor Tsai, an assistant professor of geophysics at Caltech and a coauthor on the new paper. 

The team also determined that the rupture reached unusual depths for this type of earthquake—diving as deep as 60 kilometers in places and delving beneath the Earth's crust into the upper mantle. This is surprising given that, at such depths, pressure and temperature increase, making the rock more ductile and less apt to fail. It has therefore been thought that if a stress were applied to such rocks, they would not react as abruptly as more brittle materials in the crust would. However, given the maze-like rupture pattern of the earthquake, the researchers believe another mechanism might be in play.

"One possible explanation for the complicated rupture is there might have been reduced friction as a result of interactions between water and the deep oceanic rocks," says Tsai. "And," he says, "if there wasn't much friction on these faults, then it's possible that they would slip this way under certain stress conditions."

Adding to the list of the quake's surprising qualities, the researchers pinpointed the rupture to a region of the seafloor where seismologists had previously considered such large earthquakes unlikely based on the geometry of identified faults. When they compared the location they had determined using source-imaging with high-resolution sonar data of the topography of the seafloor, the team found that the earthquake did not involve what they call "the usual suspect faults."

"This part of the oceanic plate has fracture zones and other structures inherited from when the seafloor formed here, over 50 million years ago," says Joann Stock, professor of geology at Caltech and another coauthor on the paper. "However, surprisingly, this earthquake just ruptured across these features, as if the older structure didn't matter at all."

Meng emphasizes that it is important to learn such details from previous earthquakes in order to improve earthquake-hazard assessment. After all, he says, "If other earthquake ruptures are able to go this deep or to connect as many fault segments as this earthquake did, they might also be very large and cause significant damage."

Along with Meng, Ampuero, Tsai, and Stock, additional Caltech coauthors on the paper, "An earthquake in a maze: compressional rupture branching during the April 11 2012 M8.6 Sumatra earthquake," are postdoctoral scholar Zacharie Duputel and graduate student Yingdi Luo. The work was supported by the National Science Foundation, the Gordon and Betty Moore Foundation, and the Southern California Earthquake Center, which is funded by the National Science Foundation and the United States Geological Survey.

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Kimm Fesenmaier
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