Stoltz Wins Synthetic Chemistry Award

Professor of Chemistry Brian Stoltz has been named the winner of the 2015 Mukaiyama Award from the Society of Synthetic Organic Chemistry, Japan. He was noted for "the discovery and development of new reactions and processes for the synthesis of natural products and non-naturally occurring bioactive structures," according to the award citation.

Stoltz's work is aimed at developing new strategies for creating complex molecules with interesting structural, biological, and physical properties. The goal is to use these complex molecules to guide the development of new reaction methodology to extend fundamental knowledge and to potentially lead to useful biological and medical applications.

The Mukaiyama Award, named in honor of Japanese synthetic chemist Teruaki Mukaiyama, comes with a $5,000 award, a medallion, and a certificate. It is given to an individual 45 years old or younger who has made outstanding contributions to synthetic organic chemistry. Each year, two winners are selected, one each from Japanese and non-Japanese nominees. Also being honored this year is Professor Shigehiro Yamaguchi of Nagoya University.


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Alumnus Eric Betzig Wins 2014 Nobel Prize in Chemistry

Eric Betzig (BS '83), a group leader at the Howard Hughes Medical Institute's Janelia Farm Research Campus in Ashburn, Virginia, has been awarded the 2014 Nobel Prize in Chemistry along with Stefan W. Hell of the Max Planck Institute for Biophysical Chemistry and William E. Moerner of Stanford University. The three were honored "for the development of super-resolved fluorescence microscopy," a method that allows for the creation of "super-images" with a resolution on the order of nanometers, or billionths of a meter. In essence, the work turns microscopy into "nanoscopy."

The technique developed by the trio overcomes the so-called Abbe diffraction limit, which describes a physical restriction on the sizes of the structures that can be resolved using optical microscopy, showing that, essentially, nothing smaller than one-half the wavelength of light, or about 0.2 microns, can be discerned by these scopes. The result of the Abbe limit is that only the larger structures within cells—organelles like mitochondria, for example—can be resolved and studied with regular microscopes but not individual proteins or even viruses. The restriction is akin to being able to observe the buildings that make up a city but not the city's inhabitants and their activities.

Betzig, building on earlier work by Hell and Moerner, found that it was possible to work around the Abbe limit to create very-high-resolution images of a sample, such as a developing embryo, by using fluorescent proteins that glow when illuminated with a weak pulse of light. Each time the sample is illuminated, a different, sparsely distributed subpopulation of fluorescent proteins will light up and, because the glowing molecules are spaced farther apart than the Abbe diffraction limit, a standard microscope would be able to capture them. Still, each of the images produced in this way has relatively low resolution—that is, they are blurry. Betzig, however realized that by superimposing many such images, he would be able to obtain a sharp super-image, in which nanoscale structures are clearly visible. The new technique was first described in a 2006 paper published in the journal Science.

After Caltech, Betzig, a physics major from Ruddock House, earned an MS (1985) and a PhD (1988) from Cornell University. He worked at AT&T Bell Laboratories until 1994, when he stepped away from academia and science to work for his father's machine tool company. Betzig returned to research in 2002 and joined Janelia in 2005.

To date, 33 Caltech alumni and faculty have won a total of 34 Nobel Prizes. Last year, alumnus Martin Karplus (PhD '54) also received the Chemistry Prize. 

Kathy Svitil
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Orchestrating the Healing Process in a Damaged Cornea

It is safe to say that the eye is an amazing biological system. One reason is its keratocyte cells—specialized cells that make up the bulk of the cornea. Unlike most of the other cells in our body, those in the cornea are transparent, making sight possible. Should something happen to make the cornea opaque, blindness results.

Sadly, injuries to the cornea do occur, sometimes in the simplest of ways, such as getting sand in one's eyes and scratching the cornea. The scar tissue that then grows to heal the cornea may have the unwanted side effect of being opaque. This does not happen, however, if the cornea and the tissue around it heal in a very orderly fashion. The question, then: Is it possible to encourage this orderly healing after an injury, thus preserving vision?

Professor of Chemical Engineering Julia Kornfield and graduate student Amy Fu are very much hoping that this is the case. To find out, they have assigned a few students, including Caltech senior and recent SURF fellow Jacqueline Masehi-Lano, to experiment with various growth factors that might inhibit the formation of scar tissue and promote orderly wound healing.

"We chose three growth factors to test because Amy Fu and I read several papers on growth factors that have been able to suppress some types of scar tissue," Masehi-Lano says. "In particular, we want to inhibit the formation of alpha smooth muscle actin, the type of stress fiber that creates opaque scars over corneal wounds. So far, the experiments I've done with cell cultures have worked pretty well, so it looks promising."

Eventually, the researchers hope to encapsulate the growth factors in a hydrogel that is reminiscent of the native cornea. "Our hydrogel starts out as a liquid and gels in situ on the eye," explains Masehi-Lano.

Masehi-Lano is enthusiastic about her experience with the SURF program. This past summer was her second in Kornfield's lab, and last year she was a recipient of an Amgen scholarship. "I'm really grateful that my mentor and my co-mentor have entrusted me with my own project and have allowed me to conduct my own experiments. And since it was my second summer in this lab, I was able to take up a leadership role by training a new SURF student," she says. "For me, SURF has gone beyond research. I've been able to improve my ability to present my research to the general public, which I think is extremely important." Indeed, Masehi-Lano was awarded the Caltech Doris S. Perpall SURF Speaking Competition for delivering the most outstanding oral research presentation.

Masehi-Lano plans to continue in bioengineering and is contemplating an MD/PhD program. "I've always been interested in the medical field, and though I'm committed to doing research," she explains, "I'd like to be able to do clinical trials and directly apply new medical technologies to people."

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Tuesday, October 7, 2014
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Caltech Researchers Receive NIH BRAIN Funding

On September 30, the National Institutes of Health (NIH) announced its first round of funding in furtherance of President Obama's "Brain Research through Advancing Innovative Neurotechnology"—or BRAIN—Initiative. Included among the 58 funded projects—all of which, according to the NIH, are geared toward the development of "new tools and technologies to understand neural circuit function and capture a dynamic view of the brain in action"—are six projects either led or co-led by Caltech researchers.

The Caltech projects are:

"Dissecting human brain circuits in vivo using ultrasonic neuromodulation"

Doris Tsao, assistant professor of biology
Mikhail Shapiro, assistant professor of chemical engineering

Tsao and Shapiro are teaming up to develop a new technology that both uses ultrasound to map and determine the function of interconnected brain networks and, ultimately, to change neural activity deep within the brain. "This would open new horizons for understanding human brain function and connectivity, and create completely new options for the noninvasive treatment of brain diseases such as intractable epilepsy, depression, and Parkinson's disease," Tsao says. "The key," Shapiro adds, "is to gain a precise understanding of the various mechanisms by which sound waves interact with neurons in the brain so we can use ultrasound to produce very specific neurological effects. We will be able to do this across the full spectrum, from molecules up to large model organisms."

"Modular nanophotonic probes for dense neural recording at single-cell resolution"

Michael Roukes, Robert M. Abbey Professor of Physics, Applied Physics, and Bioengineering
Thanos Siapas, professor of computation and neural systems

Roukes, Siapas, and their colleagues at Columbia University and Baylor College of Medicine propose to build ultra-dense arrays of miniature light-emitting and light-sensing probes using advanced silicon "chip" technology that permits their production en masse. These probes open the new field of integrated neurophotonics, Roukes says, and will permit simultaneous recording of the electrical activity of hundreds of thousands to, ultimately, millions of neurons, with single-cell resolution, in any given region of the brain. "The instrumentation we'll develop will enable us to observe the trafficking of information, in vivo, in brain circuits on an unprecedented scale, and to correlate this activity with behavior," he says.

"Time-Reversal Optical Focusing for Noninvasive Optogenetics"

Changhuei Yang, professor of electrical engineering, bioengineering, and medical engineering
Viviana Gradinaru, assistant professor of biology

Deep-brain stimulation has been used successfully for nearly two decades for the treatment of epilepsy, Parkinson's disease, chronic pain, depression, and other disorders. Current systems rely on electrodes implanted deep within the brain to modify the firing pattern of specific clusters of neurons, bringing them back into a more normal pattern. Yang and Gradinaru are working together on a method that would use only light waves to noninvasively activate light-sensitive molecules and precisely guide the firing of nerves. Biological tissues are opaque due to the scattering of light waves, and that scattering makes it impossible to finely focus a laser beam deep into brain tissue. The researchers hope to use an optical "time-reversal" trick previously developed by Yang to counteract the scattering, allowing light beams to be targeted to specific locations within the brain. "The technology to be developed in this project has the potential for wide-ranging applications, including noninvasive deep brain stimulation and precise incisionless laser surgery," he says.

"Integrative Functional Mapping of Sensory-Motor Pathways"

Michael H. Dickinson, Esther M. and Abe M. Zarem Professor of Bioengineering

As in other animals, locomotion in the fruit fly is a complicated process involving the interplay of sensory systems and motor circuits in the brain. Dickinson and his colleagues hope to decipher just how the brain uses sensory information to guide movements by developing a system to record the activity of large numbers of individual neurons from across the brains of fruit flies, as the flies fly in flight simulator or walk on a treadmill and are simultaneously exposed to various sights and sounds. Understanding sensory–motor integration, he says, should lead to a better understanding of human disorders, including Parkinson's disease, stroke, and spinal cord injury, and aid in the design and optimization of robotic prosthetic limbs and prosthetic devices that restore sight and other senses.

"Establishing a Comprehensive and Standardized Cell Type Characterization Platform"

David J. Anderson, Seymour Benzer Professor of Biology; Investigator, Howard Hughes Medical Institute (co-PI)

In collaboration with Hongkui Zeng and colleagues at the Allen Institute for Brain Science in Seattle, Anderson will help to develop a detailed, publicly available database characterizing the genetic, physiological, and morphological features of the various cell types in the brain that are involved in circuits controlling sensations and emotions. Understanding the cellular building blocks of brain circuits, the researchers say, is crucial for figuring out how those circuits can malfunction in disease. In particular, Anderson's lab will focus on the cells of the brain's hypothalamus and amygdala—structures that are vital to emotions and behavior, and involved in human psychiatric disorders such as post-traumatic stress disorder, anxiety, and depression. "This project will serve as a model for hub-and-spoke collaborations between academic laboratories and the Allen Institute, permitting access to their valuable resources and technologies while advancing the field more broadly," Anderson says.

"Vertically integrated approach to visual neuroscience: microcircuits to behavior"

Markus Meister, Lawrence A. Hanson, Jr. Professor of Biology (co-PI)

This project, led by Hyunjune Sebastian Seung of Princeton University, will use genetic, electrophysiological, and imaging tools to identify and map the neural connections of the retina, the light-sensing tissue in the eye, and determine their roles in visual perception and behavior. "Here we are shooting for a vertically integrated understanding of a neural system," Meister says. "The retina offers such a fantastic degree of experimental access that one can hope to bridge all scales of organization, from molecules to cells to microcircuits to behavior. We hope that success here can eventually serve as a blueprint for understanding other parts of the brain." Knowing the neural mechanisms for vision can also influence technological applications, such as new algorithms for computer vision, or the development of retinal prostheses for the treatment of blindness.

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Sensing Neuronal Activity With Light

For years, neuroscientists have been trying to develop tools that would allow them to clearly view the brain's circuitry in action—from the first moment a neuron fires to the resulting behavior in a whole organism. To get this complete picture, neuroscientists are working to develop a range of new tools to study the brain. Researchers at Caltech have developed one such tool that provides a new way of mapping neural networks in a living organism.

The work—a collaboration between Viviana Gradinaru (BS '05), assistant professor of biology and biological engineering, and Frances Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry—was described in two separate papers published this month.

When a neuron is at rest, channels and pumps in the cell membrane maintain a cell-specific balance of positively and negatively charged ions within and outside of the cell resulting in a steady membrane voltage called the cell's resting potential. However, if a stimulus is detected—for example, a scent or a sound—ions flood through newly open channels causing a change in membrane voltage. This voltage change is often manifested as an action potential—the neuronal impulse that sets circuit activity into motion.

The tool developed by Gradinaru and Arnold detects and serves as a marker of these voltage changes.

"Our overarching goal for this tool was to achieve sensing of neuronal activity with light rather than traditional electrophysiology, but this goal had a few prerequisites," Gradinaru says. "The sensor had to be fast, since action potentials happen in just milliseconds. Also, the sensor had to be very bright so that the signal could be detected with existing microscopy setups. And you need to be able to simultaneously study the multiple neurons that make up a neural network."

The researchers began by optimizing Archaerhodopsin (Arch), a light-sensitive protein from bacteria. In nature, opsins like Arch detect sunlight and initiate the microbes' movement toward the light so that they can begin photosynthesis. However, researchers can also exploit the light-responsive qualities of opsins for a neuroscience method called optogenetics—in which an organism's neurons are genetically modified to express these microbial opsins. Then, by simply shining a light on the modified neurons, the researchers can control the activity of the cells as well as their associated behaviors in the organism.

Gradinaru had previously engineered Arch for better tolerance and performance in mammalian cells as a traditional optogenetic tool used to control an organism's behavior with light. When the modified neurons are exposed to green light, Arch acts as an inhibitor, controlling neuronal activity—and thus the associated behaviors—by preventing the neurons from firing.

However, Gradinaru and Arnold were most interested in another property of Arch: when exposed to red light, the protein acts as a voltage sensor, responding to changes in membrane voltages by producing a flash of light in the presence of an action potential. Although this property could in principle allow Arch to detect the activity of networks of neurons, the light signal marking this neuronal activity was often too dim to see.

To fix this problem, Arnold and her colleagues made the Arch protein brighter using a method called directed evolution—a technique Arnold originally pioneered in the early 1990s. The researchers introduced mutations into the Arch gene, thus encoding millions of variants of the protein. They transferred the mutated genes into E. coli cells, which produced the mutant proteins encoded by the genes. They then screened thousands of the resulting E. coli colonies for the intensities of their fluorescence. The genes for the brightest versions were isolated and subjected to further rounds of mutagenesis and screening until the bacteria produced proteins that were 20 times brighter than the original Arch protein.

A paper describing the process and the bright new protein variants that were created was published in the September 9 issue of the Proceedings of the National Academy of Science.

"This experiment demonstrates how rapidly these remarkable bacterial proteins can evolve in response to new demands. But even more exciting is what they can do in neurons, as Viviana discovered," says Arnold.

In a separate study led by Gradinaru's graduate students Nicholas Flytzanis and Claire Bedbrook, who is also advised by Arnold, the researchers genetically incorporated the new, brighter Arch variants into rodent neurons in culture to see which of these versions was most sensitive to voltage changes—and therefore would be the best at detecting action potentials. One variant, Archer1, was not only bright and sensitive enough to mark action potentials in mammalian neurons in real time, it could also be used to identify which neurons were synaptically connected—and communicating with one another—in a circuit.

The work is described in a study published on September 15 in the journal Nature Communications.

"What was interesting is that we would see two cells over here light up, but not this one over there—because the first two are synaptically connected," Gradinaru says. "This tool gave us a way to observe a network where the perturbation of one cell affects another."

However, sensing activity in a living organism and correlating this activity with behavior remained the biggest challenge. To accomplish this goal Gradinaru's team worked with Paul Sternberg, the Thomas Hunt Morgan Professor of Biology, to test Archer1 as a sensor in a living organism—the tiny nematode worm C. elegans. "There are a few reasons why we used the worms here: they are powerful organisms for quick genetic engineering and their tissues are nearly transparent, making it easy to see the fluorescent protein in a living animal," she says.

After incorporating Archer1 into neurons that were a part of the worm's olfactory system—a primary source of sensory information for C. elegans—the researchers exposed the worm to an odorant. When the odorant was present, a baseline fluorescent signal was seen, and when the odorant was removed, the researchers could see the circuit of neurons light up, meaning that these particular neurons are repressed in the presence of the stimulus and active in the absence of the stimulus. The experiment was the first time that an Arch variant had been used to observe an active circuit in a living organism.

Gradinaru next hopes to use tools like Archer1 to better understand the complex neuronal networks of mammals, using microbial opsins as sensing and actuating tools in optogenetically modified rodents.

"For the future work it's useful that this tool is bifunctional. Although Archer1 acts as a voltage sensor under red light, with green light, it's an inhibitor," she says. "And so now a long-term goal for our optogenetics experiments is to combine the tools with behavior-controlling properties and the tools with voltage-sensing properties. This would allow us to obtain all-optical access to neuronal circuits. But I think there is still a lot of work ahead."

One goal for the future, Gradinaru says, is to make Archer1 even brighter. Although the protein's fluorescence can be seen through the nearly transparent tissues of the nematode worm, opaque organs such as the mammalian brain are still a challenge. More work, she says, will need to be done before Archer1 could be used to detect voltage changes in the neurons of living, behaving mammals.

And that will require further collaborations with protein engineers and biochemists like Arnold.

"As neuroscientists we often encounter experimental barriers, which open the potential for new methods. We then collaborate to generate tools through chemistry or instrumentation, then we validate them and suggest optimizations, and it just keeps going," she says. "There are a few things that we'd like to be better, and through these many iterations and hard work it can happen."

The work published in both papers was supported with grants from the National Institutes of Health (NIH), including an NIH/National Institute of Neurological Disorders and Stroke New Innovator Award to Gradinaru; Beckman Institute funding for the BIONIC center; grants from the U.S. Army Research Office as well as a Caltech Biology Division Training Grant and startup funds from Caltech's President and Provost, and the Division of Biology and Biological Engineering; and other financial support from the Shurl and Kay Curci Foundation and the Life Sciences Research Foundation.

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