Category Archives: California Institute of Technology

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Enzyme speeds how ocean locks away carbon

Scientists have found that a common enzyme can speed up—by 500 times—the rate-limiting part of the chemical reaction that helps the Earth lock away, or sequester, carbon dioxide in the ocean.

“While the new paper is about a basic chemical mechanism, the implication is that we might better mimic the natural process that stores carbon dioxide in the ocean,” says lead author Adam Subhas, a California Institute of Technology (Caltech) graduate student.

Simple problem, complex answer

The researchers used isotopic labeling and two methods for measuring isotope ratios in solutions and solids to study calcite—a form of calcium carbonate—dissolving in seawater and measure how fast it occurs at a molecular level.

scanning electron microscope image of calcite
Scanning electron microscope image of calcite. (Credit: Adam Subhas/Caltech)

It all started with a very simple, very basic problem: measuring how long it takes for calcite to dissolve in seawater.

“Although a seemingly straightforward problem, the kinetics of the reaction is poorly understood,” says Berelson, professor of earth sciences at the University of Southern California Dornsife College of Letters, Arts, and Sciences.

Calcite is a mineral made of calcium, carbon, and oxygen that is more commonly known as the sedimentary precursor to limestone and marble. In the ocean, calcite is a sediment formed from the shells of organisms, like plankton, that have died and sunk to the seafloor. Calcium carbonate is also the material that makes up coral reefs—the exoskeleton of the coral polyp.

As atmospheric carbon dioxide levels have risen past 400 parts per million—a symbolic benchmark for climate scientists confirming that the effects of the greenhouse gas in the atmosphere will be felt for generations to come—the surface oceans have absorbed more and more of that carbon dioxide.

This is part of a natural buffering process—the oceans act as a major reservoir of carbon dioxide. At the present time, they hold roughly 50 times as much of the greenhouse gas as the atmosphere.

“We decided to tackle this problem because it’s kind of embarrassing, the state of knowledge expressed in the literature…”

However, there is a second, slower, buffering process that removes carbon dioxide from the atmosphere.

Carbon dioxide is an acid in seawater, just as it is in carbonated sodas (which is part of why they eat away at your tooth enamel). The acidified surface ocean waters will eventually circulate to the deep where they can react with the dead calcium carbonate shells on the sea floor and neutralize the added carbon dioxide.

This process will take tens of thousands of years to complete, however, and meanwhile, the ever-more acidic surface waters eat away at coral reefs. But how quickly will the coral dissolve?

“We decided to tackle this problem because it’s kind of embarrassing, the state of knowledge expressed in the literature,” says Adkins, a professor of geochemistry and global environmental science at Caltech. “We can’t tell you how quickly the coral is going to dissolve.”

‘One of those rare moments’

Earlier methods relied on measuring the change in pH in the seawater as calcium carbonate dissolved, and inferring dissolution rates from that. (As calcium carbonate dissolves, it raises the pH of water, making it less acidic.) Subhas and Adkins instead opted to use isotopic labeling.

Carbon atoms exist in two stable forms in nature. About 98.9 percent of it is carbon-12, which has six protons and six neutrons. About 1.1 percent is carbon-13, with one extra neutron.

Giant icebergs store high levels of carbon

Subhas and Adkins engineered a sample of calcite made entirely of the rare carbon-13, and then dissolved it in seawater. By measuring the change in the ratio of carbon-12 to carbon-13 in the seawater over time, they were able to quantify the dissolution at a molecular level. Their method proved to be about 200 times more sensitive than comparable techniques for studying the process.

On paper, the reaction is fairly straightforward: Water plus carbon dioxide plus calcium carbonate equals dissolved calcium and bicarbonate ions in water. In practice, it is complex.

“Somehow, calcium carbonate decides to spontaneously slice itself in half. But what is the actual chemical path that reaction takes?” Adkins says.

Studying the process with a secondary ion mass spectrometer (which analyzes the surface of a solid by bombarding it with a beam of ions) and a cavity ringdown spectrometer (which analyzes the 13C/12C ratio in solution), Subhas discovered that the slow part of the reaction is the conversion of carbon dioxide and water to carbonic acid.

“This reaction has been overlooked,” Subhas says. “The slow step is making and breaking carbon-oxygen bonds. They don’t like to break; they’re stable forms.”

Armed with this knowledge, the team added the enzyme carbonic anhydrase—which helps maintain the pH balance of blood in humans and other animals—and were able to speed up the reaction by orders of magnitude.

“This is one of those rare moments in the arc of one’s career where you just go, ‘I just discovered something no one ever knew,’” Adkins says.

Forests on mountains store more carbon

A paper about the work appears online in the Proceedings of the National Academy of Sciences.

Additional coauthors are from Caltech; the USC; and the Hebrew University of Jerusalem. The National Science Foundation, the Resnick Sustainability Institute at Caltech, the Rothenberg Innovation Initiative (RI2), and the Linde Center for Global Environmental Science supported this research.

Source: Caltech

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Better light detector can see more colors

Engineers have developed a light detector that combines two disparate technologies to distinguish different wavelengths (colors) of light, including both visible and infrared wavelengths, at high resolution.

The new device incorporates both nanophotonics, which manipulates light at the nanoscale, and thermoelectrics, which translates temperature differences directly into electron voltage.

light detector illustration
Artist’s representation of a conceptual design for the color detector, which uses thermoelectric structures with with arrays of nanoscale wires that absorb different wavelengths of light based on their width. (Credit: Harry Atwater, Kelly Mauser/Caltech)

Light detectors that distinguish between different colors of light or heat are used in a variety of applications, including satellites that study changing vegetation and landscape on the earth and medical imagers that distinguish between healthy and cancerous cells based on their color variations.

The new detector operates about 10 to 100 times faster than current comparable thermoelectric devices and is capable of detecting light across a wider range of the electromagnetic spectrum than traditional light detectors.

In traditional light detectors, incoming photons of light are absorbed in a semiconductor and excite electrons that are captured by the detector. The movement of these light-excited electrons produces an electric current—a signal—that can be measured and quantified.

While effective, this type of system makes it difficult to “see” infrared light, which is made up of lower-energy photons than those in visible light.

Because the new detectors are potentially capable of capturing infrared wavelengths of sunlight and heat that cannot be collected efficiently by conventional solar materials, the technology could lead to better solar cells and imaging devices.

Technique detects coherence in incoherent light

“In nanophotonics, we study the way light interacts with structures that are much smaller than the optical wavelength itself, which results in extreme confinement of light. In this work, we have combined this attribute with the power conversion characteristics of thermoelectrics to enable a new type of optoelectronic device,” says Harry Atwater, corresponding author of the study, a professor of applied physics and materials science at the California Institute of Technology, and the director of the Joint Center for Artificial Photosynthesis (JCAP).

Atwater’s team built materials with nanostructures that are hundreds of nanometers wide—smaller even than the wavelengths of light that represent the visible spectrum, which ranges from about 400 to 700 nanometers.

The researchers created nanostructures with a variety of widths, that absorb different wavelengths—colors—of light. When these nanostructures absorb light, they generate an electric current with a strength that corresponds to the light wavelength that is absorbed.

The detectors were fabricated in a cleanroom, where the team created subwavelength structures using a combination of vapor deposition (which condenses atom-thin layers of material on a surface from an element-rich mist) and electron beam lithography (which then cuts nanoscale patterns in that material using a focused beam of electrons).

The structures, which resonate and generate a signal when they absorb photons with specific wavelengths, were created from alloys with well-known thermoelectric properties, but the research is applicable to a wide range of materials, the authors say.

Squid skin inspires eye-like photodetector

“This research is a bridge between two research fields, nanophotonics and thermoelectrics, that don’t often interact, and creates an avenue for collaboration,” says graduate student Kelly Mauser, lead author of the study. “There is a plethora of unexplored and exciting application and research opportunities at the junction of these two fields.”

The findings are described in a paper appearing in the journal Nature Nanotechnology. A Department of Energy Office of Science grant funded this research.

Source: Caltech

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Injection sends ‘genetic cargo’ to neurons all over the body

Researchers have developed new virus-based vectors that can deliver “genetic cargo” to cells past the blood-brain barrier and in neurons throughout the body, potentially making way for new treatments for diseases like Parkinson’s.

Viruses have evolved to be highly effective vehicles for delivering genes into cells. Seeking to take advantage of these traits, scientists can reprogram viruses to function as vectors, capable of carrying their genetic cargo of choice into the nuclei of cells in the body. Such vectors have become critical tools for delivering genes to treat disease or to label neurons and their connective fibers with fluorescent colors to map out their locations.

virus labels enteric nervous system
The researchers used the engineered viral vector AAV-PHP.S to label neurons lining the digestive tract with a cocktail of three distinct fluorescent proteins. Due to the stochastic uptake of viruses encoding either a blue, green or red fluorescent protein, cells are labeled with a wide range of hues. This multicolor approach can be used to differentiate neighboring neurons for morphology and tracing studies. (Credit: Chan et al., Gradinaru Lab; Nature Neuroscience)

Because viral vectors have been stripped of their own genes and, thereby, of their ability to replicate, they are no longer infectious. Therefore, achieving widespread gene delivery with the vectors is challenging. This is especially true for gene delivery to hard to reach organs like the brain, where viral vectors have to make their way past the so-called blood-brain barrier, or to the peripheral nervous system, where neurons are dispersed across the body.

Now, to enable widespread gene delivery throughout the central and peripheral nervous systems, researchers have developed two new variants of a vector based on an adeno-associated virus (AAV): one that can efficiently ferry genetic cargo past the blood-brain barrier; and another that is efficiently picked up by peripheral neurons residing outside the brain and spinal cord, such as those that sense pain and regulate heart rate, respiration, and digestion.

Both vectors are able to reach their targets following a simple injection into the bloodstream. The vectors are customizable and could potentially be used as part of a gene therapy to treat neurodegenerative disorders that affect the entire central nervous system, such as Huntington’s disease, or to help map or modulate neuronal circuits and understand how they change during disease.

“We have now developed a new collection of viruses and tools to study the central and peripheral nervous systems,” says Viviana Gradinaru, assistant professor of biology and biological engineering.

“We are now able to get highly efficient brain-wide delivery with just a low-dose systemic injection, access neurons in difficult-to-reach regions, and precisely label cells with multiple fluorescent colors to study their shapes and connections.”

Gradinaru and her team modified the external surface of an AAV developed in 2016, engineering the virus’s shell, or capsid, to allow it to more efficiently deliver genes to cells in the brain and spinal cord following intravenous injection. They named the new virus AAV-PHP.eB.

The team also developed an additional capsid variant they call AAV-PHP.S, which is able to transduce peripheral neurons.

Injected virus protects mice from HIV

“Neurons outside of the central nervous system have many functions, from relaying sensory information to controlling organ function, but some of these peripheral neural circuits are not yet well understood,” says Ben Deverman, senior research scientist and director of the Beckman Institute’s CLOVER (CLARITY, Optogenetics, and Vector Engineering Research) Center.

“The AAV-PHP.S vector that we developed could help researchers study the activity and function of specific types of neurons within peripheral circuits using genetically-encoded sensors and tools to modulate neuronal firing with light or designer drugs, respectively,” he says.

The new AAV vectors can also deliver genes that code for colorful fluorescent proteins; such proteins are useful in identifying and labeling cells. In this process, multiple AAVs—each carrying a distinct color—are mixed together and injected into the bloodstream.

When they reach their target neurons, each neuron receives a unique combination of colors, thereby giving it a visually distinct hue that makes it easier for the researchers to distinguish its fine details from those of its neighbors.

Furthermore, the team devised a technique to control the number of neurons labeled—labeling too many neurons makes it impossible to distinguish individual ones—that allows researchers to visualize individual neuron shapes and trace their connecting fibers through intact tissues using another technology the Gradinaru laboratory has helped develop, known as tissue clearing.

“Usually, when researchers want a mouse or other animal model to express fluorescent proteins in certain cells, they need to develop genetically modified animals that can take months to years to make and characterize,” says former graduate student and first author Ken Chan. “Now with a single injection, we can label specific cells with a variety of colors within weeks after the injection.”

How viruses change shape to enter host cells

“For our new systemic viral vectors—AAV PHP.S and AAV PHP.eB—there are many potential uses, from mapping circuits in the periphery and fast screening of gene regulatory elements to genome editing with powerful tools such as CRISPR-Cas9,” says Gradinaru.

“But perhaps the most exciting implication is that our tools, when paired with appropriate activity modulator genes, could enable non-invasive deep brain modulation for the treatment of neurological diseases such as Parkinson’s disease,” she says.

The National Institutes of Health, the Presidential Early Career Award for Scientists and Engineers, the Heritage Medical Research Institute, the Beckman Institute and Rosen Center at Caltech, the Gordon and Betty Moore Foundation, the Shurl & Kay Curci Foundation, the Hereditary Disease Foundation, the Friedreich’s Ataxia Research Alliance (FARA) and FARA Australasia, and the Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office provided funding for the study.

A paper describing the research appears online in the journal Nature Neuroscience.

Source: Caltech

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Ultra-thin camera design doesn’t need a lens

Traditional cameras—even those on the thinnest of cell phones—cannot be truly flat due to their optics: lenses that require a certain shape and size in order to function.

A new camera design replaces the lenses with an ultra-thin optical phased array (OPA) that does computationally what lenses do using large pieces of glass: it manipulates incoming light to capture an image.

Lenses have a curve that bends the path of incoming light and focuses it onto a piece of film or, in the case of digital cameras, an image sensor. The OPA has a large array of light receivers, each of which can individually add a tightly controlled time delay (or phase shift) to the light it receives, enabling the camera to selectively look in different directions and focus on different things.

“Here, like most other things in life, timing is everything. With our new system, you can selectively look in a desired direction and at a very small part of the picture in front of you at any given time, by controlling the timing with femto-second—quadrillionth of a second—precision,” says Ali Hajimiri, professor of electrical engineering and medical engineering at California Institute of Technology and principal investigator of a paper in OSA Technical Digest.

“We’ve created a single thin layer of integrated silicon photonics that emulates the lens and sensor of a digital camera, reducing the thickness and cost of digital cameras. It can mimic a regular lens, but can switch from a fish-eye to a telephoto lens instantaneously—with just a simple adjustment in the way the array receives light.”

Camera prototype is thinner than a dime

Phased arrays, which are used in wireless communication and radar, are collections of individual transmitters, all sending out the same signal as waves. These waves interfere with each other constructively and destructively, amplifying the signal in one direction while canceling it out elsewhere. So, an array can create a tightly focused beam of signal, which can be steered in different directions by staggering the timing of transmissions made at various points across the array.

A similar principle is used in reverse in an optical phased array receiver, which is the basis for the new camera. Light waves that are received by each element across the array cancel each other from all directions, except for one. In that direction, the waves amplify each other to create a focused “gaze” that can be electronically controlled.

“What the camera does is similar to looking through a thin straw and scanning it across the field of view. We can form an image at an incredibly fast speed by manipulating the light instead of moving a mechanical object,” says graduate student Reza Fatemi, the paper’s lead author.

Last year, Hajimiri’s team rolled out a one-dimensional version of the camera that was capable of detecting images in a line, such that it acted like a lensless barcode reader but with no mechanically moving parts.

New camera uses just 1 photon per pixel

This year’s advance was to build the first two-dimensional array capable of creating a full image. This first 2D lensless camera has an array composed of just 64 light receivers in an 8 by 8 grid. The resulting image has low resolution—but the system represents a proof of concept for a fundamental rethinking of camera technology, researchers say.

“The applications are endless,” says graduate student and coauthor Behrooz Abiri. “Even in today’s smartphones, the camera is the component that limits how thin your phone can get. Once scaled up, this technology can make lenses and thick cameras obsolete. It may even have implications for astronomy by enabling ultra-light, ultra-thin enormous flat telescopes on the ground or in space.”

“The ability to control all the optical properties of a camera electronically using a paper-thin layer of low-cost silicon photonics without any mechanical movement, lenses, or mirrors, opens a new world of imagers that could look like wallpaper, blinds, or even wearable fabric,” says Hajimiri.

The team will next work on scaling up the camera by designing chips that enable much larger receivers with higher resolution and sensitivity.

Source: Caltech

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Copper gets us closer to using CO2 pollution as fuel

A new study describes the mechanics behind an early key step in artificially activating carbon dioxide so that it can rearrange itself to become the liquid fuel ethanol.

Solving this chemical puzzle may one day lead to cleaner air and renewable fuel.

The scientists’ ultimate goal is to convert harmful carbon dioxide (CO2) in the atmosphere into beneficial liquid fuel. Currently, it is possible to make fuels out of CO2—plants do it all the time—but researchers are still trying to crack the problem of artificially producing the fuels at large enough scales to be useful.

“Quantum mechanics…takes us closer to the goal of converting carbon dioxide to fuels and other useful materials.”

Theorists at Caltech used quantum mechanics to predict what was happening at atomic scales, while experimentalists at the Department of Energy’s (DOE) Lawrence Berkeley National Lab (Berkeley Lab) used X-ray studies to analyze the steps of the chemical reaction.

“One of our tasks is to determine the exact sequence of steps for breaking apart water and CO2 into atoms and piecing them back together to form ethanol and oxygen,” says William Goddard professor of chemistry, materials science, and applied physics, who led the Caltech team. “With these new studies, we have better ideas about how to do that.”

The metal copper is at the heart of the reaction for converting CO2 to fuel. Copper is a catalyst—a material used to activate and speed up chemical reactions—and, while it aids in the production of ethanol when exposed to CO2 and water, it is not efficient enough to make large quantities of ethanol.

At Berkeley Lab, researchers exposed a thin foil sheet of copper to CO2 gas and water at room temperature. They found that the copper bound CO2 weakly and that adding water activated the CO2 by bending it into the shape needed to ultimately form the ethanol. However, when the theorists at Caltech used quantum mechanics and computer models to predict the atomic-level details of this reaction, they found that pure copper would not bind the CO2 and that water would not activate it.

This left both teams scratching their heads until they noticed that the copper in the experiments contained tiny amounts of oxygen beneath its surface. The theorists went back to their quantum mechanics equations, adding in a tiny amount of sub-surface oxygen, and were happy to find their calculations all agreed with the experiments.

“We do our experiments virtually in computers,” says research scientist Hai Xiao. “And this allows us to trace how the electrons and atoms rearrange themselves in the reaction, and thus unravel the correlation between the fundamental structure and the activity.”

Molecular ‘leaf’ uses sun to turn CO2 into fuel

The theorists also predicted that when too much oxygen was present, the CO2 would not be activated. The experimentalists deliberately added extra oxygen into the mix and confirmed this prediction.

As reported in the Proceedings of the National Academy of Sciences, subsequent X-ray studies helped further narrow down the role of the oxygen in the reaction. “Having oxygen atoms just beneath the surface—a suboxide layer—is a critical aspect to this,” says Ethan Crumlin, a scientist at Berkeley Lab. “The X-ray work brought new clarity to determining the right amount of this subsurface oxygen—and its role in interactions with CO2 gas and water—to improve the reaction.”

The scientists say that the presence of the oxygen in the copper causes some of the copper to become positively charged and this, in turn, stabilizes the CO2 so that it can bind to water and take on the bent configuration essential to eventually making ethanol.

Copper catalyst makes ethanol without crops

Based on the new findings, the Caltech researchers then used quantum mechanics to predict ways to make the reaction even more efficient. In a second paper, also to appear in PNAS, they report that a copper surface that is striped with both neutral and positively charged copper will better speed the reaction along. The team is now using this strategy, called a Metal-Embedded-in-Oxygen-Matrix (MEOM), to predict the best oxide material—either copper or something new—to place next to the neutral copper strips to achieve the fastest reaction.

“Quantum mechanics lets us find the best ways to arrange the atoms and takes us closer to the goal of converting carbon dioxide to fuels and other useful materials,” says Goddard.

The scientists are part of the Joint Center for Artificial Photosynthesis (JCAP), a DOE Energy Innovation Hub, whose goal is to convert CO2 into high-value chemical products like liquid fuels. Caltech leads JCAP in partnership with Berkeley Lab, the Stanford Linear Accelerator Center (SLAC), and UC campuses at San Diego and Irvine. The DOE Office of Basic Energy Science and JCAP funded the work.

Source: Caltech

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These neurons let us wake up in the middle of the night

Researchers have identified a group of neurons that may keep us awake even when we want to sleep.

The findings, from research with mice, have implications for treating insomnia, oversleeping, and sleep disturbances that accompany other neuropsychiatric disorders such as depression.

Biologist Viviana Gradinaru and her team wanted to know: How do we overcome tiredness in the face of a looming deadline or rouse ourselves in the dead of night to feed a crying baby? In other words, in the face of so-called salient stimuli, how do we override the natural drive to sleep?

DRNDA neurons
Dopaminergic neurons genetically engineered to express fluorescing genes. The fluorescence is used to measure activity of the neurons, which have been implicated in the sleep/wake cycle. (Credit: Gradinaru laboratory/UC Santa Barbara)

“To answer this question, we decided to examine a region of the brain, called the dorsal raphe nucleus, where there are an under-studied group of dopamine neurons called dorsal raphe nucleus neurons, or DRNDA neurons,” says Gradinaru, an assistant professor of biology and biological engineering and director of the Center for Molecular and Cellular Neuroscience of the Tianqiao and Chrissy Chen Institute for Neuroscience at the California Institute of Technology.

“People who have damage in this part of their brain have been shown to experience excessive daytime sleepiness, but there was not a good understanding of the exact role of these neurons in the sleep/wake cycle and whether they react to internal or external stimuli to influence arousal,” she says.

The team studied DRNDA neurons in mice, which are a model organism for studying the human brain. First, the team measured DRNDA activity while the animals encountered salient stimuli, such as the arrival of a potential mating partner, a sudden unpleasant sensation, or food.

The DRNDA neurons were highly active during these events, which led the researchers to theorize that the neurons send signals of salience and arousal, which can then modulate the state of sleep or wakefulness.

“We then measured DRNDA activity throughout the sleep/wake cycle and found that these neurons are least active when the animal is sleeping and increase in activity as the animal is waking up,” says Ryan Cho, a graduate student and the first author of the paper.

“We aimed to discover whether this was just a correlation or if the activity of the neurons was actually causing changes in sleep-wake states,” he says.

Fixing lousy sleep could keep us healthy longer

The researchers used a technique called optogenetics to engineer DRNDA cells to be stimulated by light. After stimulating these neurons with light during the time that the animal would normally sleep, Gradinaru and her team found that the mouse woke up from sleep and remained awake.

The reverse was true when the activity of DRNDA was chemically silenced—the animal was likely to fall asleep, even in the face of motivationally important stimuli, such as the odor of a predator or a mating partner. This implied that activity of the DRNDA neurons truly governed sleep-wake behaviors.

Finally, the researchers examined the role of these neurons in awaking due to external stimuli. The neurons’ activity was silenced with optogenetics, and a loud noise was played while the animals were asleep. Whereas control mice often woke up, the mice with blocked DRNDA often ignored the sound and remained asleep.

“These experiments showed us that DRNDA cells are necessary for full wakefulness in the face of important stimuli in mice,” Gradinaru says. “DRNDA neurons are found analogously in humans, and while they have not been studied in depth, their degeneration has been correlated with excessive daytime sleepiness in patients with neurodegenerative disorders such as multiple systems atrophy and Lewy body dementia.

“Further work is necessary to establish causation in humans and to test the potential of the DRNDA as a therapeutic target for insomnia or oversleeping, and for sleep disturbances that accompany other psychiatric disorders such as depression, bipolar disorder, and schizophrenia,” Gradinaru adds.

Is too much sleep an early sign of dementia?

The study appears in the journal Neuron. The National Institutes of Health, the NIH’s National Institute on Aging, the Heritage Medical Research Institute, the Pew Charitable Trusts, the Michael J. Fox Foundation, the Caltech-Gwangju Institute of Science and Technology exchange program, and the Alfred P. Sloan Foundation provided funding for the work.

Source: California Institute of Technology

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How a ‘stuck’ genetic switch makes leukemia worse

Researchers have found new ways to block a protein responsible for halting the production of red and white blood cells in leukemia patients, potentially making way for new treatments for the deadly cancer.

In a particularly aggressive form of leukemia, called acute myeloid leukemia, a genetic switch that regulates the maturation of blood stem cells into red and white blood cells goes awry. Normally, this switch leads to appropriate numbers of white and red blood cells. But patients with acute myeloid leukemia end up with a dangerous accumulation of blood stem cells and a lack of red and white blood cells—cells that are needed to supply the body with oxygen and fight infections.

In the new study, published in the Proceedings of the National Academy of Sciences, the researchers demonstrate new ways to impede the protein that helps control this genetic switch, called DPF2, potentially rendering acute myeloid leukemia more treatable. They report new structural and functional details about a fragment of DPF2. This new information reveals targets for the development of drugs that would block the protein’s function.

Sitting on the switch

In healthy individuals, the protein stops the production of red and white blood cells when they do not need to be replaced. That is, it turns the switch off. But the protein can be overproduced in acute myeloid leukemia patients. The protein basically sits on the switch, preventing it from turning back on to make the blood cells as needed. Patients who overproduce DPF2 have a particularly poor prognosis.

“Many human diseases, including cancers, arise because of malfunctioning genetic switches,” says André Hoelz, an author of the study and a professor of chemistry at Caltech. “Elucidating how they work at atomic detail allows us to begin the process of custom tailoring drugs to inactivate them and in many cases that is a significant step towards a cure.”

Red and white blood cells are constantly regenerated from blood stem cells, which reside in our bone marrow. Like other stem cells, blood stem cells can live forever. It is only when they become differentiated into specific cell types, such as red and white blood cells, that they then become mortal, or acquire the ability to die after a certain period of time.

Block molecule to ‘decimate’ childhood leukemia cells

“Our bodies use a complex series of genetic switches to differentiate a blood stem cell into many different cell types. These differentiated cells then circulate in the blood and serve a variety of different functions. When these cells reach the end of their lifespan they need to be replaced,” says Hoelz. “This is somewhat like replacing used tires on a car.”

Looking closer at DPF2

To investigate the role of DPF2 and learn more about how it controls the genetic switch for making blood cells, the Hoelz group partnered with Stephen D. Nimer, coauthor of the paper and director of the Sylvester Comprehensive Cancer Center, and his team.

First, Ferdinand Huber and Andrew Davenport—both graduate students at Caltech in the Hoelz group and co-first authors of the new study—obtained crystals of a portion of the DPF2 protein containing a domain known as a PHD finger, which stands for planet homeodomain.

They then used X-ray crystallography, a process that involves exposing protein crystals to high-energy X-rays, to solve the structure of the PHD finger domain. The technique took place at the Stanford Synchrotron Radiation Lightsource, using a dedicated beamline of Caltech’s Molecular Observatory.

The results reveal how DPF2 binds to a DNA-protein complex, called the nucleosome, to block the production of red and white blood cells. The protein “reads” various signals displayed on the nucleosome surface by adopting a shape that fits various modifications on the nucleosome complex, like the different shaped pieces of a jigsaw puzzle. Once the protein binds to this DNA locus, DPF2 turns off the switch that regulates blood cell differentiation.

The next step was to see if DPF2 could be blocked in human blood stem cells in the lab. Sarah Greenblatt, a postdoctoral associate in Nimer’s group and co-first author of the study, used the structural information from Hoelz’s group to create a mutated version of the protein. The Nimer group then introduced the mutated protein in blood stem cells, and found that the mutated DPF2 could no longer bind to the nucleosome. In other words, DPF2 could no longer inactivate the switch for making blood cells.

How a rabbit virus could help treat leukemia

“The mutated DPF2 was unable to bind to specific regions in the genome and could not halt blood stem cell differentiation,” says Huber. “Whether DPF2 can also be blocked in the cancer patients themselves remains to be seen.” The researchers say a structural socket in DPF2, one of the puzzle-piece-like regions identified in the new study, is a good target for candidate drugs.

The Boehringer Ingelheim Fonds, a National Institutes of Health Research Service Award, the National Cancer Institute of the National Institutes of Health, the Howard Hughes Medical Research Institute, the Heritage Medical Research Institute, Caltech startup funds, the Albert Wyrick V Scholar Award of the V Foundation for Cancer Research, a Kimmel Scholar Award of the Sidney Kimmel Foundation for Cancer Research, and the Camille & Henry Dreyfus Foundation funded the study. Other authors are from the University of Miami and the Memorial Sloan Kettering Cancer Center.

Source: California Institute of Technology

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Faster tumor test would cut repeat surgeries

A new imaging technology could help surgeons removing breast cancer lumps confirm that they have cut out the entire tumor—reducing the need for additional surgeries.

About 300,000 new cases of invasive breast cancer are discovered annually. Of these, 60 to 75 percent of patients undergo breast-conserving surgery, also called lumpectomies. These surgeries attempt to remove the entire tumor while retaining as much of the undamaged breast tissue as possible. In contrast, a mastectomy removes the entire breast.

“…we could analyze the tumor right in the operating room, and know immediately whether more tissue needs to be removed.”

The extracted tissue then goes to a lab where it is separated into thin slices, stained with a dye to highlight key features, and analyzed. If tumor cells show up on the surface of the tissue sample, it indicates that the surgeon has cut through, not around, the tumor—meaning that a portion of the tumor remains and the patient will need follow-up surgery to have more tissue removed.
After a week or two waiting for lab results, 20 to 60 percent of patients find out that they need a second surgery to have more tissue removed. But, “what if we could get rid of the waiting?,” asks Lihong Wang, professor of medical engineering and electrical engineering at California Institute of Technology.

“With 3D photoacoustic microscopy, we could analyze the tumor right in the operating room, and know immediately whether more tissue needs to be removed.”

Wang’s lab invented 3D photoacoustic microscopy. PAM excites a tissue sample with a low-energy laser, which causes the tissue to vibrate. The system measures the ultrasonic waves emitted by the vibrating tissue. Because nuclei vibrate more strongly than surrounding material, PAM reveals the size of nuclei and the packing density of cells. Cancerous tissue tends to have larger nuclei and more densely packed cells.

As reported in the journal Science Advances, PAM produces images capable of highlighting cancerous features, with no slicing or staining required.

Surgery extends lives of women with Stage IV breast cancer

Although Wang’s team has focused primarily on breast cancer tumors, his work has potential applications for any analysis of excised tumors, like those with melanoma and pancreatic cancer. In a proof-of-concept scan described in the new paper, PAM analyzed a sample in about three hours. Comparable traditional microscopy takes about seven hours to achieve the same results.

Wang says the analysis time could be cut down to 10 minutes or less with the addition of faster laser pulse repetition and parallel imaging. This would make the technology useful for clinical applications.

“Because the device never directly touches a patient, there will be fewer regulatory hurdles to overcome before gaining FDA approval for use by surgeons,” Wang says. “Potentially, we could make this tool available to surgeons within several years.”

The National Institutes of Health and the Siteman Cancer Center funded the work. Wang conducted this research while his Optical Imaging Laboratory was located at Washington University in St. Louis. He moved the lab to Caltech in January 2017.

Source: Caltech

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Laser and sound offer hi-res peek into live animal

Medical engineers can now take a live look at the inner workings of a small animal with enough resolution to see active organs, flowing blood, circulating melanoma cells, and firing neural networks.

The technique, dubbed single-impulse panoramic photoacoustic computed tomography (SIP-PACT), uses both light and ultrasound to peer inside living animals.

In Nature Biomedical Engineering, the engineers describe how this hybrid imaging technology can provide a full cross-sectional view of a small animal’s internal functions in real time.

Traditional light-based microscopy provides fast, high-resolution images that retain important functional information based on the wavelengths of light (i.e., colors) the tissue absorbs, reflects, or emits. A significant amount of that light is scattered as it travels through tissue, however, so these methods are limited to depths of less than a couple of millimeters.

Photoacoustic imaging combines the abilities of multiple imaging techniques into one platform. It uses extremely short laser bursts that safely cause cells or other light absorbers to emit ultrasound waves, which then travel unimpeded back through the tissue to sensors that translate the signal into an image.

Using this technique, medical engineers are able to discern delicate features inside the body because different types of molecules absorb light differently. For example, hemoglobin (which defines the color of blood) absorbs more light than the tissue around it, creating a contrast between oxygenated and de-oxygenated blood that makes it possible to take color images of arteries and veins in vivo.

“Photoacoustic tomography combines light and sound synergistically for high-resolution imaging of molecular contrast,” says Wang, professor of medical engineering and electrical engineering at California Institute of Technology. Wang conducted this research while the Optical Imaging Laboratory was located at Washington University in St. Louis. He moved the lab to Caltech in January 2017.

To test osteoporosis drugs, make bones transparent

“Photoacoustic imaging has been highly expected to get real-time whole-body imaging of a small animal with rich functional information,” says Junjie Yao, formerly of the Optical Imaging Laboratory, now of Duke University. “With this advance, researchers can easily watch as drugs are distributed throughout an animal and track how different organs respond,” Yao says, referring to the technique’s ability to track individual molecules as they flow through the blood stream.

Ultrasound waves easily travel through tissue, providing a much more in-depth view, but do not have the ability to discern a tissue’s chemical components and therefore do not capture important information that can be conveyed by light-based imaging. Magnetic resonance imaging (MRI) can also see deep into tissue, but requires a strong magnetic field and often takes seconds to minutes to form an image. Limits to the amount of radiation a subject can tolerate makes X-ray imaging and positron emission tomography (PET) impractical for long-term use.

Photoacoustic tomography, on the other hand, avoids ionizing radiation altogether and uses only a safe dose of nonionizing energy. As such, it is safe to use on living tissue repeatedly, the engineers say.

“It’s basically compressing one second’s worth of summer noon sunlight over a fingernail area into a single nanosecond,” says Yao. “When the laser hits a cell, the energy causes it to heat up a tiny bit and expand instantaneously, creating an ultrasonic wave. It’s like the difference between pushing on something to slowly move it and striking it to cause a vibration.”

The result is an imaging technique that can peer up to five centimeters into the typical biological tissue and generate images with sub-millimeter-level resolution, while retaining the functional information provided by traditional optical microscopy.

This ‘needle’ beam could mean super-sharp ultrasound

“This penetration range enables functional imaging of whole bodies of small animals. This capability is expected to enable all kinds of biological studies in small animals and to accelerate drug discovery,” Wang says.

Wang and his colleagues have been developing photoacoustic tomography for more than 10 years. This latest iteration adds increased speed and panoramic views to the imaging technology’s repertoire. The engineers have built a circular ultrasonic detector and a fast data-acquisition system that can triangulate the origin of an ultrasonic wave from anywhere within the body of a small animal. And with the help of a fast laser, the upgraded device can image the full cross-section of an adult rat 50 times per second, providing detailed movies of its inner workings with 120-micrometer resolution.

“The panoramic effect provides information from all directions and all angles, so you do not lose any information from each laser shot,” Yao says. “You can see the dynamics of the body in action—the pumping of the heart, the dilation of arteries, the functioning of various tissues.”

The paper describes how the engineers use these abilities to track cancerous melanoma cells as they travel through the blood vessels of a mouse. They also demonstrate the ability to watch the entire brain in real time.

“We think that this technology holds great potential for both pre-clinical imaging and clinical translation,” Yao says.

The National Institutes of Health supported the work.

Source: Caltech

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Rosetta_740

Scientists solve mystery of comets spewing O2

Scientists have solved a nagging space mystery: why comets expel oxygen gas, the same gas we breathe.

The discovery that comets produce oxygen gas—also referred to as molecular oxygen or O2—was announced in 2015 by researchers studying the comet 67P/Churyumov-Gerasimenko with the European Space Agency’s Rosetta spacecraft.

The mission unexpectedly found abundant levels of molecular oxygen in the comet’s atmosphere. Molecular oxygen in space is highly unstable, as it prefers to pair up with hydrogen to make water, or carbon to make carbon dioxide. In fact, O2 has only been detected twice before in space in star-forming nebulas.

67P/Churyumov-Gerasimenko
The Rosetta spacecraft took this image of 67P/Churyumov-Gerasimenko. This image has been enhanced to bring out the details of the comet’s activity.
(Credit: ESA/Rosetta/NAVCAM)

Scientists have proposed that the molecular oxygen on comet 67P/Churyumov-Gerasimenko might have thawed from its surface after having been frozen inside the comet since the dawn of the solar system 4.6 billion years ago.

But questions persisted because some scientists believed the oxygen should have reacted with other chemicals over all that time.

This star is like ‘time travel’ to our early solar system

Konstantinos P. Giapis, a professor of chemical engineering at California Institute of Technology, began looking at the Rosetta data because the chemical reactions happening on the comet’s surface were similar to those he has been performing in the lab for the past 20 years.

Giapis studies chemical reactions involving high-speed charged atoms, or ions, colliding with semiconductor surfaces as a means to create faster computer chips and larger digital memories for computers and phones.

“I started to take an interest in space and was looking for places where ions would be accelerated against surfaces,” he says. “After looking at measurements made on Rosetta’s comet, in particular regarding the energies of the water molecules hitting the comet, it all clicked. What I’ve been studying for years is happening right here on this comet.”

In a new Nature Communications study, Giapis and postdoctoral scholar Yunxi Yao demonstrate in the lab how the comet could be producing oxygen. Basically, water vapor molecules stream off the comet as sun heats the cosmic body.

Ultraviolet light from the sun ionizes, or charges, the water molecules, and then the sun’s wind blows the ionized water molecules back toward the comet. When the water molecules hit the comet’s surface, which contains oxygen bound in materials such as rust and sand, the molecules pick up another oxygen atom from the surface and O2 is formed.

How oxygen ‘lit the fuse’ for life on Earth

In other words, the molecular oxygen found by Rosetta need not be primordial after all but may be produced in real time on the comet.

“We have shown experimentally that it is possible to form molecular oxygen dynamically on the surface of materials similar to those found on the comet,” Yao says.

“We had no idea when we built our laboratory setups that they would end up applying to the astrophysics of comets,” says Giapis. “This original chemistry mechanism is based on the seldom-considered class of Eley-Rideal reactions, which occur when fast-moving molecules, water in this case, collide with surfaces and extract atoms residing there, forming new molecules. All necessary conditions for such reactions exist on comet 67P.”

Other astrophysical bodies, such as planets beyond our solar system, or exoplanets, might also produce molecular oxygen with a similar “abiotic” mechanism—without the need for life. This may influence how researchers search for signs of life on exoplanets in the future.

“Oxygen is an important molecule, which is very elusive in interstellar space,” says astronomer Paul Goldsmith of JPL. Goldsmith is the NASA project scientist for the European Space Agency’s Herschel mission, which made the first confirmed detection of molecular oxygen in space in 2011.

“This production mechanism studied in Professor Giapis’s laboratory could be operating in a range of environments and shows the important connection between laboratory studies and astrochemistry.”

The National Science Foundation/Department of Energy Partnership for Basic Plasma Science and Engineering funded the work.

Source: Caltech

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