Seven from Caltech Elected to National Academy of Sciences

Three Caltech professors and four Caltech alumni have been elected to the prestigious National Academy of Sciences (NAS). The announcement was made Tuesday, May 3.

Raymond Deshaies is a professor of biology, investigator at the Howard Hughes Medical Institute, and executive officer for molecular biology. Deshaies's work focuses on understanding the basic biology of protein homeostasis, the mechanisms that maintain a normal array of functional proteins within cells and organisms. He is the founder of Caltech's Proteome Exploration Laboratory to study and sequence proteomes, which are all of the proteins encoded by a genome.

John Eiler is the Robert P. Sharp Professor of Geology and professor of geochemistry, as well as the director of the Caltech Microanalysis Center. Eiler uses geochemistry to study the origin and evolution of meteorites and the earth's rocks, atmosphere, and interior. Recently, his team published a paper detailing how dinosaurs' body temperatures can be deduced from isotopic measurements of their eggshells.

Ares Rosakis is the Theodore von Kármán Professor of Aeronautics and Mechanical Engineering in the Division of Engineering and Applied Science. His research interests span a wide spectrum of length and time scales and range from the mechanics of earthquake seismology, to the physical processes involved in the catastrophic failure of aerospace materials, to the reliability of micro-electronic and opto-electronic structures and devices.

Deshaies, Eiler, and Rosakis join 70 current Caltech faculty and three trustees as members of the NAS. Also included in this year's new members are four alumni: Ian Agol (BS '92), Melanie S. Sanford (PhD '01), Frederick J. Sigworth (BS '74), and Arthur B. McDonald (PhD '70).

The National Academy of Sciences is a private, nonprofit organization of scientists and engineers dedicated to the furtherance of science and its use for the general welfare. It was established in 1863 by a congressional act of incorporation signed by Abraham Lincoln that calls on the academy to act as an official adviser to the federal government, upon request, in any matter of science or technology.

A full list of new members is available on the academy website at: http://www.nasonline.org/news-and-multimedia/news/may-3-2016-NAS-Electio...

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Three faculty members and four alumni have been elected to the National Academy of Sciences.
Wednesday, May 11, 2016
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American Academy of Arts and Sciences Elects Two from Caltech

The American Academy of Arts and Sciences has elected two Caltech professors—Hirosi Ooguri and Rob Phillips—as fellows. The American Academy is one of the nation's oldest honorary societies; this class of members is its 236th, and it includes a total of 213 scholars and leaders representing such diverse fields as academia, business, public affairs, the humanities, and the arts.

Hirosi Ooguri is the director of the Walter Burke Institute for Theoretical Physics and the Fred Kavli Professor of Theoretical Physics and Mathematics in the Division of Physics, Mathematics and Astronomy. He works on quantum field theory and superstring theory, aiming to invent new theoretical tools to solve fundamental questions in physics.

Rob Phillips is the Fred and Nancy Morris Professor of Biophysics and Biology and has appointments in the Division of Engineering and Applied Science and the Division of Biology and Biological Engineering. He focuses on the physical biology of the cell using biophysical theory as well as single-molecule and single-cell experiments.

Ooguri and Phillips join 86 current Caltech faculty as members of the American Academy. Also included in this year's list are two Caltech trustees, David Lee (PhD '74) and Ron Linde (MS '62, PhD '64); as well as three additional alumni: Gerard Fuller (MS '77, PhD '80), Melanie Sanford (PhD '01), and Robert Schoelkopf (PhD '95).

Founded in 1780 by John Adams, James Bowdoin, John Hancock, and other scholar-patriots, the academy aims to serve the nation by cultivating "every art and science which may tend to advance the interest, honor, dignity, and happiness of a free, independent, and virtuous people." The academy has elected as fellows and foreign honorary members "leading thinkers and doers" from each generation, including George Washington and Ben Franklin in the 18th century, Daniel Webster and Ralph Waldo Emerson in the 19th, and Albert Einstein and Woodrow Wilson in the 20th. This year's class of fellows includes novelist Colm Tóibín, La Opinión publisher and CEO Monica Lozano, jazz saxophonist Wayne Shorter, former Botswanan president Festus Mogae, and autism author and spokesperson Temple Grandin.

A full list of new members is available on the academy website at www.amacad.org/members.

The new class will be inducted at a ceremony on October 8, 2016, in Cambridge, Massachusetts.

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Hirosi Ooguri and Rob Phillips have been elected as members of the American Academy of Arts and Sciences.

Mapping Neurons to Improve the Treatment of Parkinson's

Because billions of neurons are packed into our brain, the neuronal circuits that are responsible for controlling our behaviors are by necessity highly intermingled. This tangled web makes it complicated for scientists to determine exactly which circuits do what. Now, using two laboratory techniques pioneered in part at Caltech, Caltech researchers have mapped out the pathways of a set of neurons responsible for the kinds of motor impairments—such as difficulty walking—found in patients with Parkinson's disease.

The work—from the laboratory of Viviana Gradinaru (BS '05), assistant professor of biology and biological engineering—was published on April 20 in the journal Neuron.

In patients with Parkinson's disease, gait disorders and difficulty with balance are often caused by the degeneration of a specific type of neuron—called cholinergic neurons—in a region of the brainstem called the pedunculopontine nucleus (PPN). Damage to this same population of neurons in the PPN is also linked to reward-based behaviors and disorders, such as addiction.

Previously, researchers had not been able to untangle the neural circuitry originating in the PPN to understand how both addictions and Parkinson's motor impairments are modulated within the same population of cells. Furthermore, this uncertainty created a barrier to treating those motor symptoms. After all, deep brain stimulation—in which a device is inserted into the brain to deliver electrical pulses to a targeted region—can be used to correct walking and balance difficulties in these patients, but without knowing exactly which part of the PPN to target, the procedure can lead to mixed results.

"The circuits responsible for controlling our behaviors are not nicely lined up, where this side does locomotion and this side does reward," Gradinaru says, and this disordered arrangement arises from the way neurons are structured. Much as a tree extends into the ground with long roots, neurons are made up of a cell body and a long string-like axon that can diverge and project elsewhere into different areas of the brain. Because of this shape, the researchers realized they could follow the neuron's "roots" to an area of the brain less crowded than the PPN. This would allow them to more easily look at the two very different behaviors and how they are implemented.

Cheng Xiao, a senior research scientist at Caltech and first author on the study, began by mapping the projections of the cholinergic neurons in the PPN of a rat using a technique developed by the Gradinaru lab called Passive CLARITY Technique, or PACT. In this technique, a solution of chemicals is applied to the brain; the chemicals dissolve the lipids in the tissue and render that region of the brain optically transparent—see-through, in other words—and able to take up fluorescent markers that can label different types of neurons. The researchers could then follow the path of the PPN neurons of interest, marked by a fluorescent protein, by simply looking through the rest of the brain.

Using this method, Gradinaru and Xiao were able to trace the axons of the PPN neurons as they extended into two regions of the midbrain: the ventral substantia nigra, a landmark area for Parkinson's disease that had been previously associated with locomotion; and the ventral tegmental area, a region of the brain that had been previously associated with reward.

Next, the researchers used an electrical recording technique to keep track of the signals sent by PPN neurons—confirming that these neurons do, in fact, communicate with their associated downstream structures in the midbrain. Then, the scientists went on to determine how this specific population of neurons affects behavior. To do this, they used a technique that Gradinaru helped develop called optogenetics, which allows researchers to manipulate neural activities—in this case, by either exciting or inhibiting the PPN neural projections in the midbrain—using different colors of light.

Using the optogenetic approach in rats, the researchers found that exciting the neuronal projections in the ventral substantia nigra would stimulate the animal to walk around its environment; by contrast, they could stop the animal's movement by inhibiting these same projections. Furthermore, they found that they could stimulate reward-seeking behavior by exciting the neuronal projections in the ventral tegmental area, but could cause aversive behavior by inhibiting these projections.

"Our results show that the cholinergic neurons from the PPN indeed have a role in controlling both behaviors," Gradinaru says. "Although the neurons are very densely packed and intermingled, these pathways are, to some extent, dedicated to very specialized behaviors." Determining which pathways are associated with which behaviors might also improve future treatments, she adds.

"In the past it's been difficult to target treatment to the PPN because the specific neurons associated with different behaviors are intermingled at the source—the PPN. Our results show that you could target the axonal projections in the substantia nigra for movement disorders and projections in the ventral tegmental area for reward disorders, as addiction is," Gradinaru says. In addition, she notes, these projections in the midbrain are much easier to access surgically than their source in the PPN.

Although this new information could inform clinical treatments for Parkinson's disease, the PPN is only one region of the brain and there are many more important examples of connectivity that need to be explored, Gradinaru says. "These results highlight the need for brain-wide functional and anatomical maps of these long-range neuronal projections; we've shown that tissue clearing and optogenetics are enabling technologies in the creation of these maps."

These results are published in a paper titled, "Cholinergic mesopontine signals govern locomotion and reward through dissociable midbrain pathways." In addition to Gradinaru and Xiao, other Caltech coauthors include Jounhong Ryan Cho, Chunyi Zhou, Jennifer Treweek, Ken Chan, Sheri McKinney, and Bin Yang. The work was supported by the National Institutes of Health, the Heritage Medical Research Institute, the Pew Charitable Trust, the Michael J. Fox Foundation, and the Sloan Foundation; the Beckman Institute supports the Resource Center on CLARITY, Optogenetics, and Vector Engineering (CLOVER) for technology development and broad dissemination.

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Caltech researchers have mapped out a circuit of neurons responsible for motor impairment in patients with Parkinson's disease.

Midnight Blue: A New System for Color Vision

The swirling skies of Vincent Van Gogh's Starry Night illustrate a mystery that has eluded biologists for more than a century—why do we perceive the color blue in the dimly lit night sky? A newly discovered mechanism of color vision in mice might help answer this question, Caltech researchers say.

The work, which was done in the laboratory of Markus Meister, Anne P. and Benjamin F. Biaggini Professor of Biological Sciences, will be published on April 14 in the print edition of the journal Nature.

In humans, vision is enabled by two types of light-sensitive photoreceptor cells called rods and cones. When these photoreceptors detect light, they send a signal to specialized neurons in the retina called retinal ganglion cells, or RGCs, which then transmit visual information to the brain by firing electrical pulses along the optic nerve.

A standard biology textbook would likely explain that vision in dim light is enabled by rods—sensitive light detectors that are only capable of producing black and white vision. Color vision, on the other hand, is enabled by cones, which are active in bright light. Humans have three types of cones, and each cone contains a different light-sensitive chemical, or pigment, that reacts to different colors, or wavelengths, of light. We have red-, green-, and blue-sensitive cones, and the brain perceives color by comparing the different signals it receives from nearby cones of each type.

To explore whether or not there were other modes of color vision, Meister and his team studied another mammal: the mouse. Previous behavioral studies indicated that mice are indeed capable of some form of color vision. As in humans, that vision is dependent on light signals picked up by cones. Mice have two types of cones—one that is sensitive to medium-wavelength green light and one that is sensitive to short-wavelength ultraviolet light (UV).

"The odd thing about the mouse is that these two kinds of cones are actually located in different parts of the retina," Meister says. "Mice look at the upper part of the visual field with their UV cones and the lower part with their green cones. We wanted to know how a mouse perceives color when any given part of the image is analyzed with only one cone or the other cone—meaning the brain can't compare the two cone signals to determine a color."

The researchers discovered that a certain type of neuron in the mouse retina, called a JAMB retinal ganglion cell (J-RGC), was critical. These J-RGCs can signal color to the brain because they fire faster in response to green light and stop firing in response to ultraviolet light. Curiously, the J-RGCs were turned on by green light even in the upper part of the visual field, which contained no green cones.

Through additional experiments, Meister and his team discovered how the J-RGC compares signals from the ultraviolet cones to signals from rods, which are also sensitive in the green part of the spectrum. This revealed, for the first time, an essential antagonistic relationship between the rods and the cones of the retina. Rods excite a neuron called a horizontal cell, which then inhibits the ultraviolet cones.

Meister and his colleague, first author Maximilian Joesch from Harvard University, wanted to determine how this color vision system would be helpful to a mouse in its natural environment. To find out, they fitted a camera with filters that would replicate the wavelengths detected by the mouse rods and cones and used it to take images of plants and materials that a mouse might encounter in nature.

Their photographic scavenger hunt yielded two materials—seeds and mouse urine—that were much more visible through the mouse's green and ultraviolet system than through human color vision. The researchers speculate that because mice need seeds for sustenance and use urine for social communication—via "urine posts," a form of territorial marking—they might use this mechanism to find food and spot neighbors.

Meister says there is reason to believe that this same pathway—from rods to horizontal cells to cones—is responsible for the human perception of the color blue in dim light. In the human retina, the horizontal cell preferentially inhibits the red and green cones, but not the blue cones.

"In really dim light, our cones don't receive enough photons to work, but they continue to emit a low-level baseline signal to the rest of the retina that is independent of light," he explains. "The rods are active, however, and through the horizontal cell they inhibit both the red and green cones. Because this baseline signal from the red and green cones is suppressed, it looks like the blue cones are more active. To the rest of the retina, it seems like everything in the field of vision is blue."  

So, perhaps Van Gogh's color choice for the night sky was a biological decision as well as an artistic one. "Color has intrigued scientists, artists, and poets throughout human civilization. Our paper adds to the understanding of how this quality of the world is perceived," Meister says.

Meister's work was published in a paper titled "A neuronal circuit for color vision based on rod-cone opponency." Funding for the work was provided by the National Institutes of Health and The International Human Frontier Science Program Organization.

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A newly discovered mechanism of color vision in mice might help answer why the dimly lit night sky has a bluish cast.
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Living—and Giving—the Caltech Dream

Growing up in Tehran, Iran, Mory Gharib (PhD '83) attended large, crowded schools. He was the kid who always raised his hand in class and asked tough questions. He craved one-on-one time with his teachers, which seldom came to pass.

So when the young Gharib read a newspaper article about a school in California with a three-to-one student-faculty ratio, it seemed almost unimaginable. Over the years, though, that school—Caltech—remained in his thoughts.

Years later, Gharib finally made it to Caltech as a graduate student. Since that time, he has built a distinguished career as a  researcher, mentor, inventor, entrepreneur, leader, and benefactor. And he has continued to search for the answers to tough questions.

"I couldn't have done this anywhere else," he says, referring to his career. "Caltech took care of me, and I have to take care of it."

In appreciation for the opportunities Caltech afforded him, Gharib—who currently serves as the Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering, director of Caltech's Graduate Aerospace Laboratories, and vice provost—has created an endowed fellowship fund to support new generations of Caltech graduate students.

Read the full story on the Caltech Giving website.

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In appreciation for the opportunities Caltech afforded him, Mory Gharib is supporting future graduate students through an endowed fellowship fund.

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