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The Swiss Army Knife of Gene Editing Gets New Control

The Swiss Army Knife of Gene Editing Gets New Control

Now, Caltech researchers have applied principles from the emerging field of dynamic RNA nanotechnology to exert logical control over CRISPR/Cas9 within living cells. By engineering RNA strands to interact and thereby change shape in response to an RNA trigger sequence, the group demonstrates the ability to switch CRISPR/Cas9 from on to off and from off to on. The work suggests a path to confine manipulation of a gene only to specific organs, tissues, or cell types within an organism.

The work was done in the laboratory of Niles Pierce, professor of applied and computational mathematics and bioengineering, and is described in a paper published on June 4, 2019, in the journal ACS Central Science.

An organism’s genome encodes complex biological processes that orchestrate the organism’s development, maintenance, and repair. Different genes encode instructions for different cellular behaviors, such as growing, communicating, and dying. Controlling gene activity is a fundamental way to change the cell’s behavior. Editing a gene, or, alternatively, turning it off or on in a given cell, provides biologists with a way to study the role of that gene, and likewise offers a promising avenue for doctors to treat disease.

Developed less than a decade ago, CRISPR/Cas9 technology has emerged as a game-changing tool for editing genomes and for controlling which genes are active and to what extent. The CRISPR/Cas9 complex is made up of two parts: Cas9, a protein that can edit genes; and the guide RNA (gRNA), a molecule that—as its name suggests—guides Cas9 to a target gene of choice. If desired, different variants of the Cas9 protein can be used to increase or decrease the level of activity of a target gene as well. In essence, a traditional gRNA executes the function “regulate gene Y,” where the choice of target gene “Y” is specified by the sequence of the gRNA, and the kind of regulation (activate, silence, edit, and so on) depends on the choice of Cas9 variant.

One of the remarkable features of CRISPR/Cas9 technology is that these capabilities work on many organisms across the tree of life, whether they be fungi, plants, or birds. However, the versatility of this approach is limited by the fact that the gRNA is “always on”—that is, it executes its function independent of the cell type it is in. As a result, additional measures are needed to restrict regulation of the selected target gene “Y” to specific cells in a specific state. For example, in a scenario where some cells are diseased, it would be useful to restrict gene regulation to only that subset of cells.

An important signature of cell type and state is provided by the collection of RNA molecules present inside the cell. In principle, detection of an RNA sequence “X” (where X is a marker for a specific tissue type or disease state) could serve as a trigger to induce editing, silencing, or activation of an independent target gene Y. For the last 15 years, the Pierce Lab has pursued this vision, seeking to engineer RNA molecules that can detect an RNA trigger sequence X and then change shape to target an independent gene Y for regulation. CRISPR/Cas9 is one of several naturally occurring biological pathways to which this technology could be applied.

Now, led by graduate students Mikhail Hanewich-Hollatz and Zhewei Chen, a team of researchers has engineered guide RNAs that are conditional, changing shape in response to the presence or absence of an RNA trigger to switch between inactive and active conformations. As a result, these so-called conditional guide RNAs (cgRNAs) can execute logical functions such as “if X then not Y” (i.e., if the trigger RNA X is present, then silence the gene target Y) or “if not X then not Y”. Unlike a traditional gRNA, cgRNAs are programmable at two levels, with the sequence of trigger X controlling where regulation occurs and the target-binding sequence controlling the subject of regulation (in other words, the identity of the target gene Y). In bacterial cells, the team has been able to demonstrate both ON-to-OFF logic with initially active cgRNAs that are turned off by an RNA trigger and OFF-to-ON logic with initially inactive cgRNAs that are turned on by an RNA trigger. Moreover, in work led by research scientist Lisa Hochrein, they were able to successfully port one cgRNA mechanism from bacterial to mammalian cells, leveraging the portability for which CRISPR/Cas9 is renowned.

The hope is that cgRNAs might someday be applied to the treatment of disease, with RNA X as a disease marker and target Y as a therapeutic target, enabling selective treatment of diseased cells while leaving healthy cells untouched. Alternatively, the same logic could enable biologists to study the role of a gene of interest at a specific location and developmental stage within an embryo.

“There is still a long way to go to realize the potential of dynamic RNA nanotechnology for engineering programmable conditional regulation in living organisms, but these results with CRISPR/Cas9 in bacterial and mammalian cells provide a proof of principle that we can build on in seeking to provide biologists and doctors with powerful new tools,” says Pierce.

The paper is titled Conditional Guide RNAs: Programmable Conditional Regulation of CRISPR/Cas Function in Bacterial and Mammalian Cells via Dynamic RNA Nanotechnology.” Graduate students Mikhail Hanewich-Hollatz and Zhewei Chen are co-first authors. In addition to Pierce, co-authors are research scientist Lisa Hochrein (MS ’09, PhD ’13) and graduate student Jining Huang. Funding was provided by the Defense Advanced Research Projects Agency, the Caltech Center for Environmental Microbial Interactions (CEMI), the National Institutes of Health, the Donna and Benjamin M. Rosen Bioengineering Center at Caltech, the Natural Sciences and Engineering Research Council of Canada, the National Science Foundation Molecular Programming Project, a Professorial Fellowship at Balliol College at the University of Oxford, and the Eastman Visiting Professorship at the University of Oxford.

Newly Discovered Giant Planet Slingshots Around Its Star

Newly Discovered Giant Planet Slingshots Around Its Star

Astronomers have discovered a planet three times the mass of Jupiter that travels on a long, egg-shaped path around its star. If this planet were somehow placed into our own solar system, it would swing from within our asteroid belt to out beyond Neptune. Other giant planets with highly elliptical orbits have been found around other stars, but none of those worlds were located at the very outer reaches of their star systems like this one.

“This planet is unlike the planets in our solar system, but more than that, it is unlike any other exoplanets we have discovered so far,” says Sarah Blunt, a Caltech graduate student and first author on the new study publishing in The Astronomical Journal. “Other planets detected far away from their stars tend to have very low eccentricities, meaning that their orbits are more circular. The fact that this planet has such a high eccentricity speaks to some difference in the way that it either formed or evolved relative to the other planets.”

The planet was discovered using the radial velocity method, a workhorse of exoplanet discovery that detects new worlds by tracking how their parent stars “wobble” in response to gravitational tugs from those planets. However, analyses of these data usually require observations taken over a planet’s entire orbital period. For planets orbiting far from their stars, this can be difficult: a full orbit can take tens or even hundreds of years.

The California Planet Search, led by Caltech Professor of Astronomy Andrew W. Howard, is one of the few groups that watches stars over the decades-long timescales necessary to detect long-period exoplanets using radial velocity. The data needed to make the discovery of the new planet were provided by the two observatories used by the California Planet Search—the Lick Observatory in Northern California and the W. M. Keck Observatory in Hawaii—and by the McDonald Observatory in Texas.

The astronomers have been watching the planet’s star, called HR 5183, since the 1990s, but do not have data corresponding to one full orbit of the planet, called HR 5183 b, because it circles its star roughly every 45 to 100 years. The team instead found the planet because of its strange orbit.

“This planet spends most of its time loitering in the outer part of its star’s planetary system in this highly eccentric orbit, then it starts to accelerate in and does a slingshot around its star,” explains Howard. “We detected this slingshot motion. We saw the planet come in and now it’s on its way out. That creates such a distinctive signature that we can be sure that this is a real planet, even though we haven’t seen a complete orbit.”

The new findings show that it is possible to use the radial velocity method to make detections of other far-flung planets without waiting decades. And, the researchers suggest, looking for more planets like this one could illuminate the role of giant planets in shaping their solar systems.

Planets take shape out of disks of material left over after stars form. That means that planets should start off in flat, circular orbits. For the newly detected planet to be on such an eccentric orbit, it must have gotten a gravitational kick from some other object. The most plausible scenario, the researchers propose, is that the planet once had a neighbor of similar size. When the two planets got close enough to each other, one pushed the other out of the solar system, forcing HR 5183 b into a highly eccentric orbit.

“This newfound planet basically would have come in like a wrecking ball,” says Howard, “knocking anything in its way out of the system.”

This discovery demonstrates that our understanding of planets beyond our solar system is still evolving. Researchers continue to find worlds that are unlike anything in our solar system or in solar systems we have already discovered.

“Copernicus taught us that Earth is not the center of the solar system, and as we expanded into discovering other solar systems of exoplanets, we expected them to be carbon copies of our own solar system,” Howard explains, “But it’s just been one surprise after another in this field. This newfound planet is another example of a system that is not the image of our solar system but has remarkable features that make our universe incredibly rich in its diversity.”

The study, titled, “Radial Velocity of an Eccentric Jovian World Orbiting at 18AU,” was funded by the National Science Foundation, NASA, Tennessee State University and the State of Tennessee, the Beatrice Watson Parrent Fellowship, the Trottier Family Foundation, and Caltech. Other Caltech authors include: BJ Fulton, a staff scientist at IPAC; former postdoctoral scholar Sean Mills (BS ’12); Erik Petigura, a former postdoctoral scholar now based at UCLA; and Arpita Roy, R.A. & G.B. Millikan Postdoctoral Scholar in Astronomy.

Materials provided by California Institute of Technology

Self-folding “Rollbot” paves the way for fully untethered soft robots

Self-folding “Rollbot” paves the way for fully untethered soft robots

The majority of soft robots today rely on external power and control, keeping them tethered to off-board systems or rigged with hard components. Now, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and the Caltech Division of Engineering and Applied Science have developed soft robotic systems, inspired by origami, that can move and change shape in response to external stimuli, paving the way for fully untethered soft robots.

The research is published in Science Robotics. The team turned to origami to create multifunctional soft robots. Through sequential folds, origami can encode multiple shapes and functionalities in a single structure. Using materials known as liquid crystal elastomers that change shape when exposed to heat, the research team 3D-printed two types of soft hinges that fold at different temperatures and thus can be programmed to fold in a specific order.

“Using hinges makes it easier to program robotic functions and control how a robot will change shape. Instead of having the entire body of a soft robot deform in ways that can be difficult to predict, you only need to program how a few small regions of your structure will respond to changes in temperature,” said Connor McMahan, a graduate student at Caltech and co-first author of the paper.

“With our method of 3D printing active hinges, we have full programmability over temperature response, the amount of torque the hinges can exert, their bending angle, and fold orientation. Our fabrication method facilitates integrating these active components with other materials,” said Arda Kotikian, a graduate student at SEAS and the Graduate School of Arts and Sciences, and co-first author of the paper.

To demonstrate this method, the team built several soft devices, including an untethered soft robot nicknamed the “Rollbot” The Rollbot begins as a flat sheet, about 8 centimeters long and 4 centimeters wide. When placed on a hot surface, about 200 degrees Celsius, one set of hinges folds and the robot curls into a pentagonal wheel.

Another set of hinges is embedded on each of the five sides of the wheel. A hinge folds when in contact with the hot surface, propelling the wheel to turn to the next side, where the next hinge folds. As they roll off the hot surface, the hinges unfold and are ready for the next cycle.

“This work demonstrates how the combination of responsive polymers in an architected composite can lead to materials with self-actuation in response to different stimuli. In the future, such materials can be programmed to perform ever more complex tasks, blurring the boundaries between materials and robots,” said Caltech’s Chiara Daraio, professor of mechanical engineering and applied physics and co-lead author of the study.

“Many existing soft robots require a tether to external power and control systems or are limited by the amount of force they can exert. These active hinges are useful because they allow soft robots to operate in environments where tethers are impractical and to lift objects many times heavier than the hinges,” says McMahan.

Another device, when placed in a hot environment, can fold into a compact shape resembling a paper clip and unfold itself when cooled.

“These untethered structures can be passively controlled,” says Kotikian. “In other words, all we need to do is expose the structures to specific temperature environments, and they will respond according to how we programmed the hinges.”

While this research only focused on temperature responses, liquid crystal elastomers can also be programmed to respond to light, pH, humidity, and other external stimuli.

“The ability to integrate active materials within 3D-printed objects enables the design and fabrication of entirely new classes of soft robotic matter,” says Jennifer A. Lewis, the Hansjorg Wyss Professor of Biologically Inspired Engineering at SEAS and co-lead author of the study.

The Science Robotics paper was co-authored by Emily C. Davidson, Jalilah M. Muhammad, and Robert D. Weeks from Harvard. It was supported by the Army Research Office, the Harvard Materials Research Science and Engineering Center through the National Science Foundation, and the NASA Space Technology Research Fellowship.

Caltech researchers take a direct image of magic-angle twisted graphene sheets

Caltech researchers take a direct image of magic-angle twisted graphene sheets

Just over a year after researchers at MIT stunned the physics world with the discovery of the “magic angle” for stacked sheets of graphene, researchers at Caltech have directly observed and studied this material using a scanning tunnelling microscope that can image electronic properties at atomic-length scales.

Understanding the “magic angle”—a specific orientation between the stacked graphene that yields special electric properties—could pave the way to realizing the dream of room-temperature superconductors, which could transmit enormous electric currents while producing zero heat.

But first: what is the magic angle? Say you take two sheets of graphene—single-atom-thick lattices of carbon atoms—and lay one atop the other to create a bilayer material, then twist one of the sheets of graphene to shift their orientation to one another. As the orientation shifts, the electronic properties of the bilayer material will change with it. In early 2018, researchers at MIT discovered that, at a certain orientation (about 1.1 degrees of relative twist), the bilayer material, surprisingly, becomes superconducting and moreover, the superconducting properties can be controlled with the electric fields. Their discovery launched a new field of research into magic angle-oriented graphene, known as “twistronics.”

Engineers and physicists at Caltech have built upon that discovery by generating an image of the atomic structure and electronic properties of magic angle-twisted graphene, yielding new insight into the phenomenon by offering a more direct way of studying it. A paper on their work was published in the journal Nature Physics on August 5.

“This pulls back the shroud on twistronics,” says Caltech’s Stevan Nadj-Perge, corresponding author of the paper and assistant professor of applied physics and materials science in the Division of Engineering and Applied Science.

Research on the magic angle requires an extreme level of precision to get the two sheets of graphene aligned at just the right angle. Old techniques for doing so necessitated embedding the graphene in an insulating material, which had the unfortunate side effect of preventing direct study of the sample. Instead, researchers had to use indirect methods of probing the graphene sample—for example, by taking measurements of how electrons flow through it. Nadj-Perge and his colleagues developed a new method of creating samples of magic angle-twisted graphene that can be used to align the two sheets of graphene very precisely while leaving it exposed for direct observation.

Using this technique, the researchers could learn more about the electronic properties of the material at the magic angle as well as study how these properties change as the twist angle moves away from the magic value. Their work provided several key insights that will guide future theoretical modeling and experiments, including the observation that the electronic correlation plays an important role near the charge-neutrality point—the angle at which the bilayer is electronically neutral.

“Previously, it was thought that correlation effects do not play a major role in charge neutrality,” Nadj-Perge says. “Closer, more detailed examination of samples like this could help us to explain why the exotic electronic effects near the magic angle exist. Once we know that, we could help pave the way for useful applications of it, perhaps even leading to room-temperature superconductivity one day.”

The paper is titled “Electronic correlations in twisted bilayer graphene near the magic angle.”Co-authors of the paper include Gil Refael, Taylor W. Lawrence Professor of Theoretical Physics; Jason Alicea, professor of theoretical physics; Caltech graduate students Youngjoon Choi, Harpreet Arora, Robert Polski, and Yiran Zhang; Caltech postdoctoral scholars Jeannette Kemmer, Yang Peng, Alex Thomson, Hechen Ren; as well as Felix von Oppen of Freie Universität Berlin in Germany; and Kenji Watanabe and Takashi Taniguchi of the National Institute for Materials Science in Japan. This research was funded by the National Science Foundation, the Kavli Nanoscience Institute, the Institute for Quantum Information and Matter at Caltech, the Walter Burke Institute for Theoretical Physics at Caltech, the Deutsche Forschungsgemeinschaft, the Kwanjeong Educational Foundation, and the Transregional Collaborative Research Center 183.

Cytoskeleton

Controlling the Shape-Shifting Skeletons of Cells

You know you have a skeleton, but did you know that your cells have skeletons, too? Cellular skeletons, or cytoskeletons, are shapeshifting networks of tiny protein filaments, enabling cells to propel themselves, carry cargo, and divide. Now, an interdisciplinary team of Caltech researchers has designed a way to study and manipulate the cytoskeleton in test tubes in the lab. Understanding how cells control movement could one day lead to tiny, bioinspired robots for therapeutic applications. The work also contributes to the development of new tools for manipulating fluids on very small scales relevant to molecular biology and chemistry.

The work is described in a paper appearing in the August 8 issue of the journal Nature.

The building blocks of the cellular cytoskeleton are thin, tube-like filaments called microtubules that can form together into three-dimensional scaffolds. Each microtubule is 1,000 times thinner than a human hair and only about 10 micrometers long (about 1,000 times smaller than a common black ant). Along with motor proteins that power movement, these incredibly small structures combine to propel the relatively large cell—like ants steering and powering a car.

An immune cell chases a bacterium

Originally taken by David Rogers at Vanderbilt University, this movie shows an immune cell chasing a bacterium. Cells like these use shape-shifting skeletons to move around.Credit: Vanderbilt University

In previous studies, researchers have taken these molecules out of the cell and put them into test tubes, where the tubules and motor proteins spontaneously group together to organize themselves into star-shaped structures called asters. How asters in a test tube are related to a cytoskeleton powering cell movement, however, is still unclear. Moreover, the collective microtubule organization demonstrated by aster formation involves interacting forces that are not entirely understood.

“What we wanted to know was: how do you get from these spontaneously forming aster structures in the lab, to a cell controlling its movement? And, how can we control these molecules the way a cell does?” says graduate student Tyler Ross, first author on the study.

Led by Ross, a team of Caltech researchers explored how to manipulate the component filaments and motor proteins outside of the cell’s natural environment. In test tubes, they linked motor proteins to light-activated proteins that are naturally found in plants, so that the tubules would only organize into asters when light was shining on them. In this way, the researchers could control when and where asters would form by projecting different patterns of light, enabling them to develop theories about the physical mechanisms underlying aster formation.

Two white asters merge together along a line

Two asters (white) form and are guided together with beams of light (dark yellow).Credit: Caltech

Controlling the asters not only allowed for the study of their formation but also enabled the team to build things out of the structures. Ross developed simple procedures of light patterns to place, move, and merge asters of various sizes. The technique offers a way to manipulate structures and study fluid dynamics at a miniscule length scale that is usually difficult to work at; fluids exhibit tricky behaviors at such small volumes.

“Generally, it’s really difficult to manipulate fluids and structures on this length scale. But this is the scale that we’re most interested in for studying cells and chemistry; all of molecular biology works on this scale,” says Ross. “Our light-based system allows us to dynamically manipulate our system. We could look through a microscope and say, ‘Okay we have enough over here, let’s start routing things over there,’ and change the light pattern accordingly. We could use aster structures in such a way that they could stir and mix solutions at very small length scales.”

Forming asters in a "plus" shape makes spiraling fluid flows around

This video illustrates how the formation of asters (white) can excite very small-scale fluid flows (black). Normally, fluids on these small scales are difficult to manipulate and characterize. Credit: Caltech

The research is a collaboration between the laboratories of Matt Thomson, assistant professor of computational biology and Heritage Medical Research Institute Investigator, and Rob Phillips, Fred and Nancy Morris Professor of Biophysics, Biology, and Physics. This collaboration, notes Thomson, enabled pivotal breakthroughs in the project, which Ross had begun in Thomson’s laboratory at UC San Francisco (UCSF) before the two came to Caltech in 2017. At Caltech, the pair teamed up with Heun Jin Lee, a staff scientist with extensive expertise in optics, to develop a specialized microscope with which they could view aster formation and direct precise patterns of light.

“This has been one of the great collaborations I’ve seen in my career,” says Thomson. “This story really speaks to the community, how you can do work across different fields and people will support and cultivate it. We had feedback from people who work in DNA nanotechnology and people who work in chemical engineering and fluid dynamics.”

The paper is titled, “Controlling Organization and Forces in Active Matter Through Optically-Defined Boundaries.” In addition to Ross, Thomson, Phillips, and Lee, other co-authors are postdoctoral scholar Zijie Qu and graduate student Rachel Banks. Funding was provided by the National Institutes of Health, the National Science Foundation, the John Templeton Foundation, the Foundational Questions Institute and the Fetzer Franklin Fund, the UCSF Center for Systems and Synthetic Biology, and the Heritage Medical Research Institute.

Materials provided by California Institute of Technology

Ghosts of Ancient Explosions Live on in Stars Today

Ghosts of Ancient Explosions Live on in Stars Today

When small, dense stars called white dwarfs explode, they produce bright, short-lived flares called Type Ia supernovae. These supernovae are informative cosmological markers for astronomers—for example, they were used to prove that the universe is accelerating in its expansion.

White dwarfs are not all the same, ranging from half of the mass of our sun to almost 50 percent more massive than our sun. Some explode in Type Ia supernovae; others simply die quietly. Now, by studying the “fossils” of long-exploded white dwarfs, Caltech astronomers have found that early on in the universe, white dwarfs often exploded at lower masses than they do today. This discovery indicates that a white dwarf could explode from a variety of causes, and does not necessarily have to reach a critical mass before exploding.

A paper about the research, led by Evan Kirby, assistant professor of astronomy, appears in the Astrophysical Journal.

Near the end of their lives, a majority of stars like our sun dwindle down into dim, dense white dwarfs, with all their mass packed into a space about the size of Earth. Sometimes, white dwarfs explode in what’s called a Type Ia (pronounced one-A) supernova.

It is uncertain why some white dwarfs explode while others do not. In the early 1900s, an astrophysicist named Subrahmanyan Chandrasekhar calculated that if a white dwarf had more than 1.4 times the mass of our sun, it would explode in a Type Ia supernova. This mass was dubbed the Chandrasekhar mass. Though Chandrasekhar’s calculations gave one explanation for why some more massive white dwarfs explode, it did not explain why other white dwarfs less than 1.4 solar masses also explode.

Studying Type Ia supernovae is a time-sensitive process; they flare into existence and fade back into darkness all within a few months. To study long-gone supernovae and the white dwarfs that produced them, Kirby and his team use a technique colloquially called galactic archaeology.

Galactic archaeology is the process of looking for chemical signatures of long-past explosions in other stars. When a white dwarf explodes in a Type Ia supernova, it pollutes its galactic environment with elements forged in the explosion—heavy elements like nickel and iron. The more massive a star is when it explodes, the more heavy elements will be formed in the supernova. Then, those elements become incorporated into any newly forming stars in that region. Just as fossils today give clues about animals that have long ceased to exist, the amounts of nickel in stars illustrates how massive their long-exploded predecessors must have been.

Using the Keck II telescope, Kirby and his team first looked at certain ancient galaxies, those that ran out of material to form stars in the first billion years of the universe’s life. Most of the stars in these galaxies, the team found, had relatively low nickel content. This meant that the exploded white dwarfs that gave them that nickel must have been relatively low mass—about as massive as the sun, lower than the Chandrasekhar mass.

Yet, the researchers found that the nickel content was higher in more recently formed galaxies, meaning that as more time went by since the Big Bang, white dwarfs had begun to explode at higher masses.

“We found that, in the early universe, white dwarfs were exploding at lower masses than later in the universe’s lifetime,” says Kirby.”It’s still unclear what has driven this change.”

Understanding the processes that result in Type Ia supernovae is important because the explosions themselves are useful tools for making measurements of the universe. Regardless of how they exploded, most Type Ia supernovae follow a well-characterized relationship between their luminosity and the time it takes for them to fade.

“We call Type Ia supernovae ‘standardizable candles.’ If you look at a candle at a distance, it will look dimmer than when it’s up close. If you know how bright it is supposed to be up close, and you measure how bright it is at a distance, you can calculate that distance,” says Kirby. “Type Ia supernovae have been very useful in calculating things like the rate of expansion of the universe. We use them all the time in cosmology. So, it’s important to understand where they come from and characterize the white dwarfs that generate these explosions.”

The next steps are to study elements other than nickel, in particular, manganese. Manganese production is very sensitive to the mass of the supernova that produces it, and therefore gives a precise way to validate the conclusions drawn by the nickel content.

Materials provided by California Institute of Technology

Ultra-thin Layers of Rust Generate Electricity from Flowing Water

Ultra-thin Layers of Rust Generate Electricity from Flowing Water

There are many ways to generate electricity—batteries, solar panels, wind turbines, and hydroelectric dams, to name a few examples. …. And now there’s rust.

New research conducted by scientists at Caltech and Northwestern University shows that thin films of rust—iron oxide—can generate electricity when saltwater flows over them. These films represent an entirely new way of generating electricity and could be used to develop new forms of sustainable power production.

Interactions between metal compounds and saltwater often generate electricity, but this is usually the result of a chemical reaction in which one or more compounds are converted to new compounds. Reactions like these are what is at work inside batteries.

In contrast, the phenomenon discovered by Tom Miller, Caltech professor of chemistry, and Franz Geiger, Dow Professor of Chemistry at Northwestern, does not involve chemical reactions, but rather converts the kinetic energy of flowing saltwater into electricity.

The phenomenon, the electrokinetic effect, has been observed before in thin films of graphene—sheets of carbon atoms arranged in a hexagonal lattice—and it is remarkably efficient. The effect is around 30 percent efficient at converting kinetic energy into electricity. For reference, the best solar panels are only about 20 percent efficient.

“A similar effect has been seen in some other materials. You can take a drop of saltwater and drag it across graphene and see some electricity generated,” Miller says.

However, it is difficult to fabricate graphene films and scale them up to usable sizes. The iron oxide films discovered by Miller and Geiger are relatively easy to produce and scalable to larger sizes, Miller says.

“It’s basically just rust on iron, so it’s pretty easy to make in large areas,” Miller says. “This is a more robust implementation of the thing seen in graphene.”

Though rust will form on iron alloys on its own, the team needed to ensure it formed in a consistently thin layer. To do that, they used a process called physical vapor deposition (PVD), which turns normally solid materials, in this case iron oxide, into a vapor that condenses on a desired surface. PVD allowed them to create an iron oxide layer 10 nanometers thick, about 10 thousand times thinner than a human hair.

When they took that rust-coated iron and flowed saltwater solutions of varying concentrations over it, they found that it generated several tens of millivolts and several microamps per cm-2.

“For perspective, plates having an area of 10 square meters each would generate a few kilowatts per hour—enough for a standard US home,” Miller says. “Of course, less demanding applications, including low-power devices in remote locations, are more promising in the near term.”

The mechanism behind the electricity generation is complex, involving ion adsorption and desorption, but it essentially works like this: The ions present in saltwater attract electrons in the iron beneath the layer of rust. As the saltwater flows, so do those ions, and through that attractive force, they drag the electrons in the iron along with them, generating an electrical current.

Miller says this effect could be useful in specific scenarios where there are moving saline solutions, like in the ocean or the human body.

“For example, tidal energy, or things bobbing in the ocean, like buoys, could be used for passive electrical energy conversion,” he says. “You have saltwater flowing in your veins in periodic pulses. That could be used to generate electricity for powering implants.”

The paper describing their findings, titled “Energy Conversion via Metal Nanolayers,” appears in the July 29 issue of the Proceedings of the National Academy of Sciences. Other co-authors include Mavis D. Boamah, Emilie H. Lozier, Paul E. Ohno, and Catherine E. Walker of Northwestern, and Jeongmin Kim, a graduate student in chemistry at Caltech.

Materials provided by the California Institute of Technology

Bubble rings

Solar Flares, Bubble Rings, and Ink Chandeliers

Engineers from Caltech have generated a computer simulation of underwater bubble rings that is so realistic it is virtually indistinguishable from a video of the real thing. The point of the research, however, lies well beyond creating next-generation computer graphics. Instead, its developers hope that the simulation can shed light on the mathematics and forces that govern such phenomena.

“When we make these abstractions, we still want to capture some fundamental truth about the universe,” says Peter Schröder, the Shaler Arthur Hanisch Professor of Computer Science and Applied and Computational Mathematics in the Division of Engineering and Applied Science, whose team built the simulation.

Bubble rings are most often seen in online videos created by scuba divers, who puff the rings out in a manner similar to smokers blowing smoke rings. Schröder’s team simulated two underwater rings of air merging and then snapping apart again. They will present their work at the International Conference and Exhibition on Computer Graphics & Interactive Techniques (SIGGRAPH), to be held in Los Angeles from July 28 to August 1.

The project began with an attempt to better understand solar flares, which are enormous loops of plasma that blast out from the surface of the sun. The creation and growth of solar flares is governed by a number of complex forces (for example, the sun’s strong magnetic field) that make modeling and understanding them difficult, Schröder says.

Because of the complexity of the problem, Schröder’s team wound up breaking it into smaller individual pieces. “If you look at videos of the sun and the eruptions on the surface of the sun, you can see these large arcs of what are called flux ropes,” Schröder says. “They twist and then turn on themselves, and there are violent events where the loop runs into itself. This is a little bit similar to when two vortex filaments—two bubble rings—meet. There is a very violent reaction where they merge or a section gets pinched off, with waves traveling along the bubble ring.”

A similar, but gentler version can be created by dropping ink into water. The ink forms a twisting doughnut shape that then branches off into what are called ink chandeliers.

Solar flares, bubble rings, and ink chandeliers all share one thing in common: twisting, fluid doughnut-like shapes that rotate around a center line. Thus, effectively modeling one of the phenomena should offer partial insight into the others, Schröder says.

“The hope of our work is to provide geometric insights. We are always looking at the geometry of things and of their behavior—in this case, we are looking at the geometry of this center curve of the bubble ring traveling and the changes in its thickness,” he says.

To measure how closely his computer simulations model reality, Schröder compares them side-by-side with videos of the real thing. Even if he doesn’t have every possible variable pinned down perfectly, if the two videos are virtually indistinguishable, he’s probably doing something right.

“Now, we have a visual comparison because there’s no way of saying, ‘Wow, you got that exactly right.’ It’s too complicated to verify quantitatively; there are too many variables. But when you see the visualization, the eye will say, ‘Yes, this is a match,'” he says. “I invite anybody to look at it and tell me whether they think it’s a match. We feel pretty good about it.”

That qualitative—rather than quantitative—analysis can seem inexact by a mathematician’s standards, but it has led to some wonderful “a-ha” moments for Schröder, when the computer simulation looks so realistic that he can be confident that the mathematics he used to build it are the ones that govern real-world phenomena.

“What drives me is finding these beautiful descriptions of something that looks terribly complicated but can be reduced to a few mathematical key concepts. Then the rest just follows from there. There’s beauty in seeing that a very simple principle all of a sudden gives rise to the complex appearance we perceive,” Schröder says.

Materials provided by California Insititute of Technology

Microbots

Microrobots Activated by Laser Pulses Show Promise For Treating Tumors

But often what ails us is inside the body and is not so easy to reach. In such cases, a treatment like surgery or chemotherapy might be called for. A pair of researchers in Caltech’s Division of Engineering and Applied Science are working on an entirely new form of treatment—microrobots that can deliver drugs to specific spots inside the body while being monitored and controlled from outside the body.

“The microrobot concept is really cool because you can get micromachinery right to where you need it,” says Lihong Wang, Caltech’s Bren Professor of Medical Engineering and Electrical Engineering. “It could be drug delivery, or a predesigned microsurgery.”

The microrobots are a joint research project of Wang and Wei Gao, assistant professor of medical engineering, and are intended for treating tumors in the digestive tract.

The microrobots consist of microscopic spheres of magnesium metal coated with thin layers of gold and parylene, a polymer that resists digestion. The layers leave a circular portion of the sphere uncovered, kind of like a porthole. The uncovered portion of the magnesium reacts with the fluids in the digestive tract, generating small bubbles. The stream of bubbles acts like a jet and propels the sphere forward until it collides with nearby tissue.

On their own, magnesium spherical microrobots that can zoom around might be interesting, but they are not especially useful. To turn them from a novelty into a vehicle for delivering medication, Wang and Gao made some modifications to them.

First, a layer of medication is sandwiched between an individual microsphere and its parylene coat. Then, to protect the microrobots from the harsh environment of the stomach, they are enveloped in microcapsules made of paraffin wax.

At this stage, the spheres are capable of carrying drugs, but still lack the crucial ability to deliver them to a desired location. For that, Wang and Gao use photoacoustic computed tomography (PACT), a technique developed by Wang that uses pulses of infrared laser light.

The infrared laser light diffuses through tissues and is absorbed by oxygen-carrying hemoglobin molecules in red blood cells, causing the molecules to vibrate ultrasonically. Those ultrasonic vibrations are picked up by sensors pressed against the skin. The data from those sensors is used to create images of the internal structures of the body.

Previously, Wang has shown that variations of PACT can be used to identify breast tumors, or even individual cancer cells. With respect to the microrobots, the technique has two jobs. The first is imaging. By using PACT, the researchers can find tumors in the digestive tract and also track the location of the microrobots, which show up strongly in the PACT images. Once the microrobots arrive in the vicinity of the tumor, a high-power continuous-wave near-infrared laser beam is used to activate them. Because the microrobots absorb the infrared light so strongly, they briefly heat up, melting the wax capsule surrounding them, and exposing them to digestive fluids. At that point, the microrobots’ bubble jets activate, and the microrobots begin swarming. The jets are not steerable, so the technique is sort of a shotgun approach—the microrobots will not all hit the targeted area, but many will. When they do, they stick to the surface and begin releasing their medication payload.

“These micromotors can penetrate the mucus of the digestive tract and stay there for a long time. This improves medicine delivery,” Gao says. “But because they’re made of magnesium, they’re biocompatible and biodegradable.”

Tests in animal models show that the microrobots perform as intended, but Gao and Wang say they are planning to continue pushing the research forward.

“We demonstrated the concept that you can reach the diseased area and activate the microrobots,” Gao says. “The next step is evaluating the therapeutic effect of them.”

Gao also says he would like to develop variations of the microrobots that can operate in other parts of the body, and with different types of propulsion systems.

Wang says his goal is to improve how his PACT system interacts with the microrobots. The infrared laser light it uses has some difficulty reaching into deeper parts of the body, but he says it should be possible to develop a system that can penetrate further.

The paper describing the microrobot research, titled, “A microrobotic system guided by photoacoustic tomography for targeted navigation in intestines in vivo,” appears in the July 24 issue of Science Robotics. Other co-authors include Zhiguang Wu, Lei Li, Yiran Yang (MS ’18), Yang Li, and So-Yoon Yang of Caltech; and Peng Hu of Washington University in St. Louis. Funding for the research was provided by the National Institutes of Health and Caltech’s Donna and Benjamin M. Rosen Bioengineering Center.

Materials provided by the California Institute of technology

Performing Chemistry in Floating Droplets

Performing Chemistry in Floating Droplets

Could chemists be ready to ditch the venerable test tube, the very symbol of chemistry in the minds of many people? Maybe not quite yet, but Caltech’s Jack Beauchamp is working on it.

Beauchamp is doing work in what he calls “lab-in-a-drop” chemistry, in which chemical reactions are performed within a drop of liquid suspended in midair through acoustic levitation.

Acoustic levitation works by creating areas of high and low pressure in the air through the use of ultrasonic transducers. These transducers act like tiny but powerful speakers that operate at a frequency above what human ears can hear. The sonic energy emitted by these transducers is focused in such a way that the high- and low-pressure zones they create form “traps” that can hold small objects in place in the air. An object placed in one of the low-pressure zones is held there by the high-pressure zones that surround it. An acoustic levitator of this sort can be constructed for about $75 from off-the-shelf parts using 3D-printing techniques.

An animated gif showing a hand place a pellet in the levitator. Graphics showing high- and low-pressure zones are superimposed.

Credit: Caltech

In a new paper, Beauchamp and his colleagues describe the use of the technique to study how a skin-cancer drug works at a chemical level. The research, he says, represents the first successful use of acoustic levitation as a “wall-less” reactor in a detailed study of chemical reactions.

In the work, Beauchamp and his team coated a droplet of water with lipids, biomolecules that make up cell membranes. They then applied an anti-cancer drug to the droplet and used a mass spectrometer to “sniff” the chemical signature given off by the droplet as the drug reacted with the lipid when illuminated with a red laser pointer.

In the experiment, the researchers added a small amount of one of two lipids, cardiolipin and POPG (1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1′-rac-glycerol)), to each drop of water. The lipids migrated to the surface of the droplet, where they organized to form a thin film that is similar in composition to the cell membrane of a living cell.

With the membrane established, a chemical called temoporfin was added to the droplet. Temoporfin, a ring-like molecule, is excited by red light. In this state, the temoporfin transfers energy to molecular oxygen, forming an excited electronic state that easily oxidizes molecules it comes into contact with, including those that make up cell membranes. This makes temoporfin useful as a treatment for some skin cancers. A doctor could apply the drug to a cancerous lesion and then illuminate it with red light, which easily shines through tissues. As the compound is illuminated and excited, it oxidizes vital cellular materials, including lipids, proteins, and nucleic acids, triggering cell death.

It was this cancer-killing process that Beauchamp wanted to study. “When you’re doing this chemistry, you’d like to be able to carry out these reactions under conditions where you don’t have any contact of the liquid with surfaces,” he says. “We achieve this goal by performing chemistry in a levitated droplet.”

The acoustic levitator allowed Beauchamp and his team to suspend in midair a 1 millimeter droplet of water containing a mixture of the lipid and temoporfin. The droplet was then illuminated by red laser light, exciting the temoporfin and causing it to oxidize the molecules of the membrane layer.

As this oxidation was occurring, a pair of high-voltage electrodes placed near the droplet pulled minute amounts of material off the droplet and into the sensor of a mass spectrometer, which provided readings that allowed researchers to deduce the molecular structures of compounds within the drop. By continually monitoring these readings, the researchers were able to see how the compounds on the surface became progressively more oxidized. By looking at these reaction products, Beauchamp says the research team could determine how the oxidation processes work.

“As far as I know, we’re the only people doing serious chemistry this way, examining the kinetics and mechanism of the reactions involved” Beauchamp says.

Acoustic levitation could find use in other fields as well, he says. As an example, he cites the research of Caltech’s Joe Parker, an assistant professor of biology and biological engineering who studies the symbiotic relationship between certain species of ants and beetles. Beauchamp says it would be possible to levitate an ant and a beetle in close proximity to one another and then use the apparatus to analyze the pheromones they emit.

The technique could have other applications as well. In collaborative studies with Caltech’s John Seinfeld, Louis E. Nohl Professor of Chemical Engineering, Beauchamp previously revealed details of the complex environmental chemistry that leads to the formation of organic aerosols in the atmosphere in studies using droplets hanging on the end of a capillary. With the new levitation methodology, that capillary would no longer be required.

The paper describing Beauchamp’s research, titled “Mass Spectrometric Study of Acoustically Levitated Droplets Illuminates Molecular-Level Mechanism of Photodynamic Therapy for Cancer Involving Lipid Oxidation,” appears in the April 23 issue of Angewandte Chemie, the flagship journal of the German Chemical Society. Beauchamp’s co-authors include Chaonan Mu, Jie Wang, and Xingxing Zhang of Nankai University, and Kevin J. Barraza, a postdoctoral scholar in chemistry at Caltech.

Materials provided by the California Institute of Technology