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

Rerouting Cancer

Cancer is capable of rapidly developing resistance to therapeutic drugs, rendering those drugs harmless—often before they have a chance to work. Now, researchers at Caltech and their colleagues have identified how at least one brain cancer, called glioblastoma multiforme (GBM), adapts so fast—and they show that by formulating the right combination of drugs, doctors could potentially overcome this resistance and stop a tumor in its tracks.

The work appears in the April 12 issue of the journal Cancer Cell.

Some cancer drugs are designed to target a cell's chemical circuitry. This network of signaling pathways controls how a healthy cell functions, but in many cancers, the pathways are hyperactivated, directly leading to the aggressive nature of the disease. By blocking a key pathway, a drug can, in principle, stop the tumor from growing.

"The concept is that if you block a key node in the pathway, then the communication can't proceed and the cells can't get the signals to divide and multiply," explains Jim Heath, the Elizabeth W. Gilloon Professor of Chemistry and co-corresponding author on the paper.

In reality, however, tumors can become resistant to a drug even if the drug works exactly as designed. With GBM, such resistance develops in almost every patient. "In some patients, you can treat with a drug that does everything you could want it to do, but you would never know that the drug hit the target because the tumor adapts so quickly," Heath says.

Some scientists have suspected that the cancer becomes resistant through Darwinian-type evolution, in a process similar to how bacteria develop resistance to antibiotics. That is, the genetic differences of certain cancer cells may make those cells resistant to a drug. Nonresistant cells are killed by the drug and their death leaves room for the naturally resistant cells—and tumors—to grow and multiply.

However, this mechanism was not what Heath and his colleagues found in studies of tissue from glioblastoma patients. Instead, the researchers discovered that the cancer cells that developed resistance to a drug were the same cells that had responded to the drug. When the drug blocks a signaling pathway in a cancer cell, they realized, the cell simply finds a detour, like a GPS navigator that reroutes to avoid traffic.

"You can block a key part," Heath says, "and the cells will respond to route around that part you blocked."

This notion of shifting pathways is not new, but the work is the first to show that the process can happen in as little as two days. In particular, the researchers found that the changes occur with a specific drug (CC214‑2) that targets a central GBM signaling-protein called mTOR. When mTOR is inhibited, certain GBM signaling pathways are repressed, but others are activated.

To map the detours, the researchers separated individual GBM cells from patient tumors and measured the levels of several key proteins in the cells. These proteins—called phosphoproteins because they are activated by the addition of a phosphoryl group to a molecule—carry signals throughout the cell. Measurements of the abundance of the proteins showed that the drug was effective.

The story was different at the single-cell level, at which Heath and his colleagues not only measured the levels of proteins in individual cells, but also the signaling between those proteins. For example, if protein A signals protein B, then the levels of A, as measured across many single cells, will correlate with the levels of B.  By measuring the presence of several such proteins, the researchers could infer the structure of the protein signaling network.

They discovered that after the drug was introduced, the cell activated new pathways that previously had been dormant. This drug-induced pathway activation suggested several combination therapies that might halt the development of drug resistance, as well as drugging strategies that would have no effect.

In mice, Heath and his team tested seven therapies or therapy combinations that they predicted would—or would not—halt resistance development. The four that they predicted would not work were, indeed, ineffectual; the three they thought would work, did. The researchers then showed that they could see similar effects in GBM patient tissues, as well as in melanoma tumor models. This kind of rapid drug adaptation by tumors may occur in many cancer types, and helps explain how cancers can develop resistance to targeted drugs so quickly, Heath says.

The good news is that, by identifying the drug-activated signaling pathways, one may be able to find drug combinations that will suppress resistance, Heath says. Eventually, he says, clinicians may be able to analyze a patient's tumor at the single-cell level to determine the best therapy strategy.

These kinds of drug combinations would likely remain a secondary therapy against cancer—used when treatments like chemotherapy, radiation, and surgery fail. But, Heath says, they are essential for staving off the resistance that has severely limited the benefits that patients currently receive from targeted therapies.

The first authors of the Cancer Cell paper, titled "Single cell phosphoproteomics resolves adaptive signaling dynamics and informs targeted combination therapy in glioblastoma," are Wei Wei (PhD '14), a visitor in chemistry at Caltech and assistant professor at UCLA, and Young Shik Shin (MS '06, PhD '11), who now works at a biotech startup. Both are former graduate students of Heath's. A third key contributor to the work was Beatrice Gini, formerly a member of the UC San Diego (UCSD) laboratory of co-corresponding author Paul Mischel and now at UC San Francisco. Other Caltech authors include Min Xue and Kiwook Hwang (PhD '13) and graduate students Jungwoo Kim and Yapeng Su. Authors also include researchers from UCSD, the University of Verona in Italy, Northwestern University, and the Celgene Corporation. Heath is board member of and holds a financial interest in IsoPlexis, a company that is commercializing a microchip technology similar to what was used for single-cell analyses in the research described. 

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A new strategy may help overcome cancer cells' drug resistance.

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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Midnight Blue: A New System for Color Vision
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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.

Biochemists Solve the Structure of Cell's DNA Gatekeeper

Caltech scientists have produced the most detailed map yet of the massive protein machine that controls access to the DNA-containing heart of the cell.

In a new study, a team led by André Hoelz, an assistant professor of biochemistry, reports the successful mapping of the structure of the symmetric core of the nuclear pore complex (NPC), a cellular gatekeeper that determines what molecules can enter and exit the nucleus, where a cell's genetic information is stored.

The study appears in the April 15, 2016 issue of the journal Science, featured on the cover.

The findings are the culmination of more than a decade of work by Hoelz's research group and could lead to new classes of medicine against viruses that subvert the NPC in order to hijack infected cells and that could treat various diseases associated with NPC dysfunction.

"The methods that we have been developing for the last 12 years open the door for tackling other large and flexible structures like this," says Hoelz. "The cell is full of such machineries but they have resisted structural characterization at the atomic level."

The NPC is one of the largest and most complex structures inside the cells of eukaryotes, the group of organisms that includes humans and other mammals, and it is vital for the survival of cells. It is composed of approximately 10 million atoms that together form the symmetric core as well as surrounding asymmetric structures that attach to other cellular machineries. The NPC has about 50 times the number of atoms as the ribosome—a large cellular component whose structure was not solved until the year 2000. Because the NPC is so big, it jiggles like a large block of gelatin, and this constant motion makes it difficult to get a clear snapshot of its structure.

In 2004, Hoelz laid out an ambitious plan for mapping the structure of the NPC: Rather than trying to image the entire assembly at once, he and his group would determine the crystal structures of each of its 34 protein subunits and then piece them together like a three-dimensional jigsaw puzzle. "A lot of people told us we were really crazy, that it would never work, and that it could not be done," Hoelz says.

Last year, the team published two papers in Science that detailed the structures of key pieces of the NPC's inner and outer rings, which are the two primary components of the NPC's symmetric core. The donut-shaped core is embedded in the nuclear envelope, a double membrane that surrounds the nucleus, creating a selective barrier for molecules entering and leaving the nucleus.

By being able to piece these crystal structures into a reconstruction of the intact human NPC obtained through a technique called electron cryotomography—in which entire isolated nuclei are instantaneously frozen, with all of their structures and molecules locked into place, and then probed with a transmission electron microscope to produce 2-D images that can be reassembled into a 3-D structure—"we bridged for the first time the resolution gap between low-resolution electron microscopy reconstructions that provide overall shape and high-resolution crystal structures that provide the precise positioning of all atoms," Hoelz says.

With these structures known, the mapping of the rest of the NPC's symmetric core came quickly. "It is just like when solving a puzzle," he says. "By placing the first piece confidently, we knew that we would eventually be able to place all of them."

As described in the new paper, Hoelz's research group now has solved the crystal structures of the last remaining components of the symmetric core's inner ring and determined where all of the rings' pieces fit in the NPC's overall structure.

To do this, the team had to first generate a complete "biochemical interaction map" of the entire symmetric core. Akin to a blueprint, this map describes the interconnections and interactions of all of the proteins, as part of a larger cellular machine. The process involved genetically modifying bacteria to produce purified samples of each of the 19 different protein subunits of the NPC's symmetric core and then combining the fragments two at a time inside a test tube to see which adhered to each other.

The team then used the completed interaction map as a guide for identifying the inner ring's key proteins and employed X-ray crystallography to determine the size, shape, and position of all of their atoms. X-ray crystallography involves shining X-rays on a crystallized sample and analyzing the pattern of rays reflected off the atoms in the crystal. The team analyzed thousands of samples at Caltech's Molecular Observatory—a facility developed with support from the Gordon and Betty Moore Foundation that includes an automated X-ray beam line at the Stanford Synchrotron Radiation Laboratory that can be controlled remotely from Caltech—and the GM/CA beam line at the Advanced Photon Source at the Argonne National Laboratory.

"We now had a clear picture of what the key jigsaw pieces of the NPC looked like and how they fit together," says Daniel Lin, a graduate student in Hoelz's lab and one of two first authors on the study.

The next step was to determine how the individual pieces fit into the larger puzzle of the NPC's overall structure. To do this, the team took advantage of an electron microscopy reconstruction of the entire human NPC published in 2015 by Martin Beck's group at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. The images from Beck's group were relatively low resolution and revealed only a rough approximation of the NPC's shape, but they still provided a critical framework onto which Hoelz's team could overlay their atomic high-resolution images, captured using X-ray crystallography. The NPC is the largest cellular structure ever pieced together using such an approach.

"We were able to use the biochemical interaction map we created to solve the puzzle in an unbiased way," Hoelz says. "This not only ensured that our pieces fit in the electron microscopy reconstruction, but that they also fit together in a way that made sense in the context of the interaction map."

Hoelz said his team is committed to solving the remaining asymmetric parts of the NPC, which include filamentous structures that serve as docking sites for so-called transport factors that ferry molecules safely through the pore and other cellular machineries that are critical for the flow of genetic information from DNA to RNA to protein.

"I suspect that things are going to move very quickly now," Hoelz says. "We know exactly what we need to do. It's like we're climbing Mount Everest for the first time, and we've made it to Camp 4. All that's left is the sprint to the summit."

Along with Hoelz and Lin, additional Caltech authors on the paper, "Architecture of the symmetric core of the nuclear pore," include research technician Emily Rundlet; Thibaud Perriches, George Mobbs, and Karsten Thierbach, all postdoctoral scholars in chemistry working in the Hoelz lab; and graduate students Ferdinand Huber and Leslie Collins. Other coauthors on the paper include former Hoelz lab member Tobias Stuwe—the second cofirst author of the paper—as well as former lab members Sandra Schilbach, Yanbin Fan, Andrew Davenport (PhD '15), and Young Jeon.

The work was supported by the National Institute of General Medical Sciences; the Caltech-Amgen Research Collaboration; the German Research Foundation; the Boehringer Ingelheim Fonds; the China Scholarship Council; Caltech startup funds; an Albert Wyrick V Scholar Award from the V Foundation for Cancer Research; a Mallinckrodt Scholar Award from the Edward Mallinckrodt Jr. Foundation; a Kimmel Scholar Award from the Sidney Kimmel Foundation; and a Camille Dreyfus Teacher-Scholar Award from the Camille & Henry Dreyfus Foundation. Hoelz is also an inaugural Heritage Principal Investigator of the Heritage Medical Research Institute for the Advancement of Medicine and Science at Caltech.

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The detailed map is the first to determine the structure of a massive protein machine with near-atomic resolution.
Tuesday, April 12, 2016
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An Up-Close View of Bacterial "Motors"

Bacteria are the most abundant form of life on Earth, and they are capable of living in diverse habitats ranging from the surface of rocks to the insides of our intestines. Over millennia, these adaptable little organisms have evolved a variety of specialized mechanisms to move themselves through their particular environments. In two recent Caltech studies, researchers used a state-of-the-art imaging technique to capture, for the first time, three-dimensional views of this tiny complicated machinery in bacteria.

"Bacteria are widely considered to be 'simple' cells; however, this assumption is a reflection of our limitations, not theirs," says Grant Jensen, a professor of biophysics and biology at Caltech and an investigator with the Howard Hughes Medical Institute (HHMI). "In the past, we simply didn't have technology that could reveal the full glory of the nanomachines—huge complexes comprising many copies of a dozen or more unique proteins—that carry out sophisticated functions."

Jensen and his colleagues used a technique called electron cryotomography to study the complexity of these cell motility nanomachines. The technique allows them to capture 3-D images of intact cells at macromolecular resolution—specifically, with a resolution that ranges from 2 to 5 nanometers (for comparison, a whole cell can be several thousand nanometers in diameter). First, the cells are instantaneously frozen so that water molecules do not have time to rearrange to form ice crystals; this locks the cells in place without damaging their structure. Then, using a transmission electron microscope, the researchers image the cells from different angles, producing a series of 2-D images that—like a computed tomography, or CT, scan—can be digitally reconstructed into a 3-D picture of the cell's structures. Jensen's laboratory is one of only a few in the entire world that can do this type of imaging.

In a paper published in the March 11 issue of the journal Science, the Caltech team used this technique to analyze the cell motility machinery that involves a structure called the type IVa pilus machine (T4PM). This mechanism allows a bacterium to move through its environment in much the same way that Spider-Man travels between skyscrapers; the T4PM assembles a long fiber (the pilus) that attaches to a surface like a grappling hook and subsequently retracts, thus pulling the cell forward.

Although this method of movement is used by many types of bacteria, including several human pathogens, Jensen and his team used electron cryotomography to visualize this cell motility mechanism in intact Myxococcus xanthus—a type of soil bacterium. The researchers found that the structure is made up of several parts, including a pore on the outer membrane of the cell, four interconnected ring structures, and a stemlike structure. By systematically imaging mutants, each of which lacked one of the 10 T4PM core components, and comparing these mutants with normal M. xanthus cells, they mapped the locations of all 10 T4PM core components, providing insights into pilus assembly, structure, and function.

"In this study, we revealed the beautiful complexity of this machine that may be the strongest motor known in nature. The machine lets M. xanthus, a predatory bacterium, move across a field to form a 'wolf pack' with other M. xanthus cells, and hunt together for other bacteria on which to prey," Jensen says.

Another way that bacteria move about their environment is by employing a flagellum—a long whiplike structure that extends outward from the cell. The flagellum is spun by cellular machinery, creating a sort of propeller that motors the bacterium through a substrate. However, cells that must push through the thick mucus of the intestine, for example, need more powerful versions of these motors, compared to cells that only need enough propeller power to travel through a pool of water.

In a second paper, published in the online early edition of the Proceedings of the National Academy of Sciences (PNAS) on March 14, Jensen and his colleagues again used electron cryotomography to study the differences between these heavy-duty and light-duty versions of the bacterial propeller. The 3-D images they captured showed that the varying levels of propeller power among several different species of bacteria can be explained by structural differences in these tiny motors.

In order for the flagellum to act as a propeller, structures in the cell's motor must apply torque—the force needed to cause an object to rotate—to the flagellum. The researchers found that the high-power motors have additional torque-generating protein complexes that are found at a relatively wide radius from the flagellum. This extra distance provides greater leverage to rotate the flagellum, thus generating greater torque. The strength of the cell's motor was directly correlated with the number of these torque-generating complexes in the cell.

"These two studies establish a technique for solving the complete structures of large macromolecular complexes in situ, or inside intact cells," Jensen says. "Other structure determination methods, such as X-ray crystallography, require complexes to be purified out of cells, resulting in loss of components and possible contamination. On the other hand, traditional 2-D imaging alone doesn't let you see where individual protein pieces fit in the complete structure. Our electron cryotomography technique is a good solution because it can be used to look at the whole cell, providing a complete picture of the architecture and location of these structures."

The work involving the type IVa pilus machinery was published in a Science paper titled "Architecture of the type IVa pilus machine." First author Yi-Wei Chang is a research scientist at Caltech; additional coauthors include collaborators from the Max Planck Institute for Terrestrial Microbiology, in Marburg, Germany, and from the University of Utah. The study was funded by the National Institutes of Health (NIH), HHMI, the Max Planck Society, and the Deutsche Forschungsgemeinschaft.

Work involving the flagellum machinery was published in a PNAS paper titled "Diverse high-torque bacterial flagellar motors assemble wider stator rings using a conserved protein scaffold." Additional coauthors include collaborators from Imperial College London; the University of Texas Southwestern Medical Center; and the University of Wisconsin–Madison. The study was supported by funding from the UK's Biotechnology and Biological Sciences Research Council and from HHMI and NIH.

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Quintessentially Caltech

How best to recognize Caltech's own Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics, and director of the Physical Biology Center for Ultrafast Science and Technology, who has served on Caltech's faculty for 40 years? President Thomas F. Rosenbaum had the answer: what he would later call a "quintessentially Caltech conference."

And so, on Friday, February 26, more than 1,000 people gathered to hear exceptional researchers, including 5 Nobel Laureates, from across disciplines consider our future as part of the full-day "Science and Society" conference that honored the career of Zewail, whom Rosenbaum called "a wizard of scientific innovation."

Read the full story and view the slideshow

Written by Alex Roth

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Caltech: A Personal Perspective

Ahmed Zewail, Nobel Laureate
Linus Pauling Professor of Chemistry and Professor of Physics, Caltech

Zewail provided an overview of his journey from a young child in Egypt to Caltech Nobel laureate. On the day he won the 1999 Nobel Prize in Physics, he recalled, Caltech president David Baltimore came to Zewail's house, but he refused to open the door. "We thought he was paparazzi," Zewail admitted.

Credit: Chris Sabanpan

The End of Disease?

Roger Kornberg, Nobel Laureate
Mrs. George A. Winzer Professor in Medicine, Stanford, School of Medicine

As advanced as we think we are, Kornberg said, scientists today understand less than 1 percent of human biology. Attracting more young people to the field of medical research is therefore critical. "Young scientists are the most likely to discover something," he said. "And numbers matter."

Credit: Chris Sabanpan

The Future of Medicine

David Baltimore, Nobel Laureate
Caltech President Emeritus
Robert Andrews Millikan Professor of Biology, Caltech

The human body can survive a maximum of roughly 120 years, according to Baltimore. He predicted a future in which scientists work to push that envelope, using gene editing "to liberate us from the process of aging" and "to perfect the human body, whatever that means."

Credit: Chris Sabanpan

The Future of Quantum Physics

H. Jeff Kimble, Member, National Academy of Sciences
William L. Valentine Professor and Professor of Physics, Caltech

Kimble's lecture about the future of quantum physics included predictions about quantum computing, quantum simulation, and quantum metrology. "Science helps hold us together and appreciate our sameness rather than our differences," he said.

 

Credit: Chris Sabanpan

Time, Einstein, and the Coolest Stuff in the Universe

William Phillips, Nobel Laureate
Physicist, National Institute of Standards and Technology
Distinguished University Professor, University of Maryland

In a hands-on demonstration, Phillips put on a pair of lab goggles and dunked a variety of items—a rose, a racquetball, several inflated balloons—into a vat of liquid nitrogen to help demonstrate his overall point: that we can create super-accurate atomic clocks by cooling down atoms to astoundingly low temperatures.

Credit: Chris Sabanpan

Inequality and World Economics

A. Michael Spence, Nobel Laureate
Philip H. Knight Professor and Dean, Emeritus
Stanford University Graduate School of Business

Spence discussed a number of global economic trends—including the decline in middle-class jobs and the rise of job-eliminating technologies—in a lecture that considered the disparities between rich and poor. "I'm a little worried about what's going on in the global economy right now and I tend to be an optimist," he said.

Credit: Chris Sabanpan

The Future of Space Exploration

Charles Elachi, NASA Outstanding Leadership Medal Recipient
Caltech Vice President
Director, Jet Propulsion Laboratory

Elachi said he believes we will establish a space station on Mars and that humans will begin visiting the planet by 2030. But, he noted, "It's important that we take care of our own planet. It's the only thing we have, at least for now."

 

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How best to recognize Caltech's own Ahmed Zewail, the Linus Pauling Professor of Chemistry and professor of physics, and director of the Physical Biology Center for Ultrafast Science and Technology, who has served on Caltech's faculty for 40 years? President Thomas F. Rosenbaum had the answer: what he would later call a "quintessentially Caltech conference."

And so, on Friday, February 26, more than 1,000 people gathered to hear exceptional researchers, including 5 Nobel Laureates, from across disciplines consider our future as part of the full-day "Science and Society" conference that honored the career of Zewail, whom Rosenbaum called "a wizard of scientific innovation."

The speakers lectured on a broad spectrum of topics, ranging from space travel to global economic inequality to what happens when five inflated balloons are stuffed into a vat of liquid nitrogen. Their talks were moderated by Nathan Gardels, editor in chief of The WorldPost, and Peter Dervan, the Bren Professor of Chemistry, who noted while introducing Zewail that they have been close friends ever since their early days starting as assistant professors together at Caltech.

"What an extraordinary day," Rosenbaum said at the conclusion of the event, held in Beckman Auditorium. "It's unusual to find a series of talks at this incredibly high level of excellence—intellectually deep and pedagogically engaging."

As many of the speakers pointed out, Zewail's list of accomplishments is staggering. He has authored some 600 articles and 16 books and was sole recipient of the 1999 Nobel Prize for his pioneering work in femtochemistry. In the post-Nobel era, he developed a new field dubbed four-dimensional electron microscopy. He has been active in global affairs, serving as the first U.S. Science Envoy to the Middle East and helping establish the Zewail City of Science and Technology in Cairo, which he hopes to turn into "the Caltech of Egypt."

"Ahmed is a very special kind of scientist," said Fiona Harrison, chair of Caltech's Division of Physics, Mathematics and Astronomy, during the conference's introductory remarks. She noted the "incredible breadth of his research" and cited a colleague's observation that "Ahmed is someone who never has average goals."

Jackie Barton, chair of Caltech's Division of Chemistry and Chemical Engineering, praised Caltech for taking a chance on Zewail four decades ago, when he was a young scientist. "He had this vision," she said. "The vision was to watch the dynamics of chemical reactions, to watch reactions happening on a faster and faster time scale, indeed to watch the making and breaking of chemical bonds."

She added: "He has this intuitive sense of the dynamical motions of atoms and molecules, their coherence, or lack thereof, as the case may be. And then he has this extraordinary attention to every detail, so that he's able to meld together theory and experiment and understand that dance, that choreography of atoms and molecules as they carry out a reaction."

To further honor Zewail, Caltech presented him with a rare book of Benjamin Franklin's speeches and scientific research—on lightning rods and the aurora borealis, among other phenomena—that is signed by Rosenbaum and all of Caltech's former presidents. Caltech Provost Ed Stolper noted that it is the only book authored by Franklin that was published during his lifetime.

As Stolper noted in his introductory remarks, the gift is a fitting one for Zewail, who has come to embody the ideal of Caltech, a place "where scientists and engineers are limited only by their imagination." He added Ahmed is one of the few scientists that, like Benjamin Franklin and Linus Pauling, not only excelled in science but has made a broader impact on society through his writings and actions.

Written by Alex Roth

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Ten Years of DNA Origami

On March 16, 2006, Research Professor of Bioengineering, Computing and Mathematical Sciences, and Computation and Neural Systems Paul Rothemund (BS '94) published a paper in Nature detailing his new method for folding DNA into shapes and patterns on the scale of a few nanometers. This marked a turning point in DNA nanotechnology, enabling precise control over designed molecular structures. Ten years later, the field has grown considerably. On March 14–16, 2016, the Division of Engineering and Applied Science will hold a symposium titled "Ten Years of DNA Origami" to honor Rothemund's contribution to the field, to survey the spectrum of research it has inspired, and to take a look at what is to come.

"Think about DNA origami as a general-purpose pegboard for organizing nanometer-sized things," Rothemund says. "Each DNA origami has 200 different attachment points, to which one can attach proteins, or tiny gold balls, or fluorescent molecules, or electrically conductive carbon nanotubes. There is no other way to juxtapose combinations of these elements into complex arrangements, and this is what researchers around the world, from biologists to physicists, are using DNA origami for. Biologists use DNA origami to position different protein enzymes next to each other, so that one enzyme can hand off its products to the next enzyme in a sort of nanoscale assembly line. Others are organizing electronic components in an attempt to make nanocircuits."

The symposium was organized by Erik Winfree, professor of computer science, computation and neural systems, and bioengineering. "This amazing Caltech invention has had a remarkable impact in molecular nanotechnology research," he says.

Talks will cover DNA nanotechnology, self-assembly and pattern formation, computational algorithms and software for origami design and analysis, applications in biology and biomedicine, applications in quantum physics, molecular motors and mechanical devices, biophysics and thermodynamics and kinetics, and more. The talks are open to the public, but attendees must first register online.

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On March 14–16, Caltech will hold a symposium to look back on achievements in the field of DNA origami and to take a look at what is to come.

Rothenberg Wins Feynman Prize

The 2016 Richard P. Feynman Prize for Excellence in Teaching has been awarded to Ellen Rothenberg, the Albert Billings Ruddock Professor of Biology.

Established in 1993, the Feynman Prize annually honors "a professor who demonstrates, in the broadest sense, unusual ability, creativity, and innovation in undergraduate and graduate classroom or laboratory teaching." Rothenberg, who has been at Caltech since joining the faculty as an assistant professor in 1982, was nominated for the prize by her students, who cited qualities such as her passion for teaching and her engagement with students as the reason for their nominations.

Rothenberg investigates the regulatory mechanisms that control blood stem cell differentiation and the development of T lymphocytes—white blood cells that play an important role in immunity. Not surprisingly, when she began at Caltech, her first teaching assignment was Immunology (Bi 114), a course that she continued to teach for 25 years, consistently receiving high ratings from her students in her teaching-quality feedback reports. In 1989, Rothenberg also introduced Caltech's first course on the molecular biology of blood development, Hematopoiesis: A Developmental System (Bi 214)—a course that she still teaches every other year.

Rothenberg recently was instrumental to changes made to the introductory biology courses at Caltech. "I was the chair of the Curriculum Committee, and I noticed that there were issues that arose for both students and faculty with the first two introductory courses," she says. Beginning in 2008, she began redeveloping and teaching these introductory courses, Cell Biology (Bi 9) and then molecular biology (Bi 8). A student's first two terms at Caltech are mandatory pass/fail, "and we discovered that the students are actually really excited to do something hard when it's on a pass/fail basis," she explains.

In a letter of nomination, one of Rothenberg's students said that she appreciated the challenge to learn more complicated material in an introductory course. "In her course, Professor Rothenberg emphasizes important concepts about molecular biology; however, she also takes time to explore higher-level concepts with incredible enthusiasm," the student said. "This introduced me to the many complex systems I could learn about while showing me how exciting biological research is. I also sit on the Curriculum Committee, which she leads, and I have seen how she constantly returns to the idea of what will help students learn best and what will train them effectively."

Another student who nominated Rothenberg wrote that "… she showed students that, contrary to what they might have heard, biology was not simply a 'memorization game,' but rather a logic puzzle. By slowly introducing us to different research techniques, she allowed us to see how we could pose and answer questions in biology ourselves."

In addition to challenging her students to learn in a new way, Rothenberg says that these introductory courses also challenged her to teach differently. Because introductory courses have larger class sizes, she says it was inherently more difficult to get to know her students. So, she found ways to connect with her students outside of class time. "She spends a lot of time with her students," one student said in a nomination, "even actively participating in recitation sections with her TAs, an unusual task for professors. She strives to improve her class every year."

Previously, Rothenberg was awarded the Biology Undergraduate Students Advisory Council Award for excellence in teaching four times, the Ferguson Prize for Undergraduate Teaching twice, and the ASCIT Award for Undergraduate Teaching twice. In addition, she has chaired the divisional Curriculum Committee for the past several years, working to rationalize the biology curriculum and to put the best teachers in place for each course. As part of her work on the Curriculum Committee, she interacts closely with the Biology Undergraduate Students Advisory Council.

"Winning this award and being recognized at an institutional level…it means a lot to me. And I'm also really humbled that I'm the first biologist ever to get the Feynman Prize," she says. "I love teaching. The greatest gift you can give someone is to share your understanding with them and to help them develop their own understanding. That incredible connection between the way you appreciate the complexity of the world and the way you can give students the tools to see things that you never saw before—it's really beautiful. And the fact that this institute has a way of valuing that is really wonderful," she adds.

The Feynman Prize has been endowed through the generosity of Caltech Associates Ione and Robert E. Paradise and an anonymous local couple. Some of the most recent winners of the Feynman Prize include Kevin Gilmartin, professor of English; Steven Frautschi, professor of theoretical physics, emeritus; and Paul Asimow, professor of geology and geochemistry.

Nominations for next year's Feynman Prize for Excellence in Teaching will be solicited in the fall. Further information about the prize can be found on the Provost's Office website.

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The 2016 Richard Feynman Prize for Excellence in Teaching has been awarded to Ellen Rothenberg, the Albert Billings Ruddock Professor of Biology.

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