Switching Senses

Caltech biologists find that leeches shift the way they locate prey in adulthood

PASADENA, Calif.—Many meat-eating animals have unique ways of hunting down a meal using their senses. To find a tasty treat, bats use echolocation, snakes rely on infrared vision, and owls take advantage of the concave feathers on their faces, the better to help them hear possible prey. Leeches have not just one but two distinct ways of detecting dinner, and, according to new findings from biologists at the California Institute of Technology (Caltech), their preferred method changes as they age.

Medicinal leeches, like many aquatic animals, use water disturbances to help them find a meal. Juvenile leeches eat the blood of fish and amphibians, while adults opt for blood meals from the more nutritious mammals. Since it was known that leeches change their food sources as they develop, the Caltech team wanted to know if the way they sense potential food changed as well. Their findings are outlined in a paper now available online in the Journal of Experimental Biology.

The group set up experiments to test how much leeches rely on each of the two sensory modalities they use to find food: hairs on their bodies that can note disturbances in the water made by prey moving through it and simple eyes that can pick up on the passing shadows that those waves make. They monitored both juvenile and adult leeches as they reacted to mechanical waves in a tank of water or to passing shadows, as well as to a combination of the two stimuli. The leeches in both age groups responded in similar ways when only one stimulus was present. But when both waves and shadows existed, the adult leeches responded solely to the waves. 

"We knew that there was a developmental switch in what kind of prey they go after," says Daniel Wagenaar, senior author of the paper and Broad Senior Research Fellow in Brain Circuitry at Caltech. "So when we saw a difference in the source of disturbances that the juveniles go after relative to the adults, we thought 'great—it's probably matching what we know.'"

However, the team was very surprised to see that the individual sensory modalities aren't modified during development to help decipher different types of prey. The leech's visual system doesn't really change as the animal matures; neither does the mechanical system. What does change, however, is the integration of the visual and mechanical cues to make a final behavioral decision.

"As they mature, the animals basically start paying attention to one sense more than the other," explains Cynthia Harley, lead author of the study and a postdoctoral scholar in biology at Caltech. She says that the team will now focus their studies on the adult leeches to learn more about how this sensory information is processed both at the behavioral and cellular levels.

Paper coauthor Javier Cienfuegos, now a freshman at Yale, contributed to the study while a high school student at the Polytechnic School, which is located next to Caltech's campus. He ran about half of the experimental trials and was "instrumental in the success of the study," says Harley.

The research outlined in the paper, "Developmentally regulated multisensory integration for prey localization in the medicinal leech," was funded by the Burroughs Wellcome Fund and the Broad Foundations.

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Building Better HIV Antibodies

Caltech biologists create neutralizing antibody that shows increased potency

PASADENA, Calif.—Using highly potent antibodies isolated from HIV-positive people, researchers have recently begun to identify ways to broadly neutralize the many possible subtypes of HIV. Now, a team led by biologists at the California Institute of Technology (Caltech) has built upon one of these naturally occurring antibodies to create a stronger version they believe is a better candidate for clinical applications.

Current advances in isolating antibodies from HIV-infected individuals have allowed for the discovery of a large number of new, broadly neutralizing anti-HIV antibodies directed against the host receptor (CD4) binding site—a functional site on the surface of the virus that allows for cell entry and infection. Using a technique known as structure-based rational design, the team modified one already-known and particularly potent antibody—NIH45-46—so that it can target the binding site in a different and more powerful way. A study outlining their process was published in the October 27 issue of Science Express.

"NIH45-46 was already one of the most broad and potent of the known anti-HIV antibodies," says Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and senior author on the study. "Our new antibody is now arguably the best of the currently available, broadly neutralizing anti-HIV antibodies."

By conducting structural studies, the researchers were able to identify how NIH45-46 interacted with gp120—a protein on the surface of the virus that's required for the successful entry of HIV into cells—to neutralize the virus. Using this information, they were able to create a new antibody (dubbed NIH45-46G54W) that is better able to grab onto and interfere with gp120. This improves the antibody's breadth—or extent to which it effectively targets many subtypes of HIV—and potency by an order of magnitude, according to Ron Diskin, a postdoctoral scholar in Bjorkman's lab at Caltech and the paper's lead author.

"Not only did we design an improved version of NIH45-46, our structural data are calling into question previous assumptions about how to make a vaccine in order to elicit such antibodies," says Diskin. "We hope that these observations will help to guide and improve future immunogen design."

By improving the efficacy of antibodies that can neutralize HIV, the researchers point to the possibility of clinical testing for NIH45-46G54W and other antibodies as therapeutic agents. It's also plausible that understanding effective neutralization by powerful antibodies may be useful in vaccine development. 

"The results uncover the structural underpinnings of anti-HIV antibody breadth and potency, offer a new view of neutralization by CD4-binding site anti-HIV antibodies, and establish principles that may enable the creation of a new group of HIV therapeutics," says Bjorkman, who is also a Howard Hughes Medical Institute investigator.

Other Caltech authors on the study, "Increasing the Potency and Breadth of an HIV Antibody by Using Structure-Based Rational Design," include Paola M. Marcovecchio, Anthony P. West, Jr., Han Gao, and Priyanthi N.P. Gnanapragasm. Johannes Scheid, Florian Klein, Alexander Abadir, and Michel Nussenweig from Rockefeller University, and Michael Seaman from Beth Israel Deaconess Medical Center in Boston also contributed to the paper. The research was funded by the Bill & Melinda Gates Foundation, the National Institutes of Health, the Gordon and Betty Moore Foundation, and the German Research Foundation.

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Caltech Professors Mark E. Davis and David A. Tirrell Elected to the Institute of Medicine

Caltech Now Has Three of the 13 Living Members of All Three Branches of the National Academies

PASADENA, Calif.—Mark E. Davis and David A. Tirrell of the California Institute of Technology (Caltech) have been elected to the Institute of Medicine (IOM), an honor that is considered among the highest in the fields of health and medicine. Both Davis and Tirrell are already members of the National Academy of Sciences and the National Academy of Engineering, making them two of only 13 living individuals who have been elected to all three branches of the National Academies.

"Both Mark and Dave have made important interdisciplinary contributions that span the fields of chemical and biomolecular engineering," says Jacqueline Barton, the Arthur and Marian Hanisch Memorial Professor of Chemistry and chair of the Division of Chemistry and Chemical Engineering at Caltech. "It is fitting that they be honored by all three academies."

Although election to all three branches of the academies is a rare distinction, Davis and Tirrell are not the first from Caltech to earn the honor—the Institute now has three faculty members and two alumni on the list of 13. Frances Arnold, the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering, and Biochemistry joined the ranks in 2008, and alumni Leroy Hood and Yuan-Cheng Fung are also on the list.

Mark Davis, the Warren and Katharine Schlinger Professor of Chemical Engineering, is a member of the experimental therapeutics program at the City of Hope Comprehensive Cancer Center. His research focuses on the design and synthesis of nanoscale materials that are designed to be combined with therapeutic molecules. These "nanomedicines" have the potential to change the way cancer is treated—by providing more targeted therapies with fewer side effects—and are currently being tested in clinical trials.

"I am honored to receive this recognition," Davis says, "as it gives us validation that the medical community appreciates our work on creating new cancer therapeutics."

Davis earned his BS, MS, and PhD at the University of Kentucky in 1977, 1978, and 1981, respectively. He joined the Caltech faculty as a professor in 1991, was named Schlinger Professor in 1993, and served as executive officer for chemical engineering from 1999 to 2004.

David Tirrell, the Ross McCollum-William H. Corcoran Professor and professor of chemistry and chemical engineering, is known for work that bridges chemistry, biology, and materials science. Tirrell has developed a method for getting bacterial cells to "read" artificial genes and then produce protein-like structures with unusual or desired properties. The new materials could be useful in biomedical applications.

"It's always nice when a group of colleagues indicates that they think the research going on in your laboratory is worthwhile," Tirrell says. "My students and postdocs work on fundamental problems in protein chemistry, usually without specific clinical objectives. But we hope that what we do might someday find its way into medical practice and into other areas of science and technology."

Tirrell received his BS from MIT in 1974 and his PhD from the University of Massachusetts in 1978. He joined Caltech's faculty in 1998 and served as chair of the Division of Chemistry and Chemical Engineering from 1999 until 2009.

The IOM was established in 1970 by the National Academy of Sciences and is recognized as "a national resource for independent, scientifically informed analysis and recommendations on human health issues."

The election of Davis and Tirrell brings Caltech's total representation in the IOM to six faculty members and two trustees. This year, 65 new members and five foreign associates were elected to the IOM, bringing the total active membership to 1,688 members and the total number of foreign associates to 102.

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Caltech Named World's Top University in New Times Higher Education Global Ranking

PASADENA, Calif.—The California Institute of Technology (Caltech) has been rated the world's number one university in the 2011–2012 Times Higher Education global ranking of the top 200 universities, displacing Harvard University from the top spot for the first time in the survey's eight-year history.

Caltech was number two in the 2010–2011 ranking; Harvard and Stanford University share the second spot in the 2011–2012 survey, while the University of Oxford and Princeton University round out the top five.

"It's gratifying to be recognized for the work we do here and the impact it has—both on our students and on the global community," says Caltech president Jean-Lou Chameau. "Today's announcement reinforces Caltech's legacy of innovation, and our unwavering dedication to giving our extraordinary people the environment and resources with which to pursue their best ideas. It's also truly gratifying to see three California schools—including my alma mater, Stanford—in the top ten."

Thirteen performance indicators representing research (worth 30% of a school's overall ranking score), teaching (30%), citations (30%), international outlook (which includes the total numbers of international students and faculty and the ratio of scholarly papers with international collaborators; 7.5%), and industry income (a measure of innovation; 2.5%) are included in the data. Among the measures included are a reputation survey of 17,500 academics; institutional, industry, and faculty research income; and an analysis of 50 million scholarly papers to determine the average number of citations per scholarly paper, a measure of research impact.

"We know that innovation is the driver of the global economy, and is especially important during times of economic volatility," says Kent Kresa, chairman of the Caltech Board of Trustees. "I am pleased that Caltech is being recognized for its leadership and impact; this just confirms what many of us have known for a long time about this extraordinary place."

"Caltech has been one of California's best-kept secrets for a long time," says Caltech trustee Narendra Gupta. "But I think the secret is out!"

Times Higher Education, which compiled the listing using data supplied by Thomson Reuters, reports that this year's methodology was refined to ensure that universities with particular strength in the arts, humanities, and social sciences are placed on a more equal footing with those with a specialty in science subjects. Caltech—described in a Times Higher Education press release as "much younger, smaller, and specialised" than Harvard—was nevertheless ranked the highest based on their metrics.

According to Phil Baty, editor of the Times Higher Education World University Rankings, "the differences at the top of the university rankings are miniscule, but Caltech just pips Harvard with marginally better scores for 'research—volume, income, and reputation,' research influence, and the income it attracts from industry. With differentials so slight, a simple factor plays a decisive role in determining rank order: money."

"Harvard reported funding increases similar in proportion to other institutions, whereas Caltech reported a steep rise (16%) in research funding and an increase in total institutional income," Baty says.

Data for the Times Higher Education's World University Rankings was provided by Thomson Reuters from its Global Institutional Profiles Project (http://science.thomsonreuters.com/globalprofilesproject/), an ongoing, multistage process to collect and validate factual data about academic institutional performance across a variety of aspects and multiple disciplines.

For a full list of the world's top 200 schools and all of the performance indicators, go to http://www.timeshighereducation.co.uk/world-university-rankings/.

# # # 

The California Institute of Technology (Caltech) is a small, private university in Pasadena that conducts instruction and research in science and engineering, with a student body of about 900 undergraduates and 1,200 graduate students. Recognized for its outstanding faculty, including several Nobel laureates, and such renowned off-campus facilities as the Jet Propulsion Laboratory, the W. M. Keck Observatory, and the Palomar Observatory, Caltech is one of the world's preeminent research centers.

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Caltech Engineers Build Smart Petri Dish

Device can be used for medical diagnostics, to image cell growth continuously

PASADENA, Calif.—The cameras in our cell phones have dramatically changed the way we share the special moments in our lives, making photographs instantly available to friends and family. Now, the imaging sensor chips that form the heart of these built-in cameras are helping engineers at the California Institute of Technology (Caltech) transform the way cell cultures are imaged by serving as the platform for a "smart" petri dish.

Dubbed ePetri, the device is described in a paper that appears online this week in the Proceedings of the National Academy of Sciences (PNAS).

Since the late 1800s, biologists have used petri dishes primarily to grow cells. In the medical field, they are used to identify bacterial infections, such as tuberculosis. Conventional use of a petri dish requires that the cells being cultured be placed in an incubator to grow. As the sample grows, it is removed—often numerous times—from the incubator to be studied under a microscope.

Not so with the ePetri, whose platform does away with the need for bulky microscopes and significantly reduces human labor time, while improving the way in which the culture growth can be recorded.

"Our ePetri dish is a compact, small, lens-free microscopy imaging platform. We can directly track the cell culture or bacteria culture within the incubator," explains Guoan Zheng, lead author of the study and a graduate student in electrical engineering at Caltech. "The data from the ePetri dish automatically transfers to a computer outside the incubator by a cable connection. Therefore, this technology can significantly streamline and improve cell culture experiments by cutting down on human labor and contamination risks."

The team built the platform prototype using a Google smart phone, a commercially available cell-phone image sensor, and Lego building blocks. The culture is placed on the image-sensor chip, while the phone's LED screen is used as a scanning light source. The device is placed in an incubator with a wire running from the chip to a laptop outside the incubator. As the image sensor takes pictures of the culture, that information is sent out to the laptop, enabling the researchers to acquire and save images of the cells as they are growing in real time. The technology is particularly adept at imaging confluent cells—those that grow very close to one another and typically cover the entire petri dish.

"Until now, imaging of confluent cell cultures has been a highly labor-intensive process in which the traditional microscope has to serve as an expensive and suboptimal workhorse," says Changhuei Yang, senior author of the study and professor of electrical engineering and bioengineering at Caltech. "What this technology allows us to do is create a system in which you can do wide field-of-view microscopy imaging of confluent cell samples. It capitalizes on the use of readily available image-sensor technology, which is found in all cell-phone cameras."

In addition to simplifying medical diagnostic tests, the ePetri platform may be useful in various other areas, such as drug screening and the detection of toxic compounds. It has also proved to be practical for use in basic research.

Caltech biologist Michael Elowitz, a coauthor on the study, has put the ePetri system to the test, using it to observe embryonic stem cells. Stem cells in different parts of a petri dish often behave differently, changing into various types of other, more specialized cells. Using a conventional microscope with its lens's limitations, a researcher effectively wears blinders and is only able to focus on one region of the petri dish at a time, says Elowitz. But by using the ePetri platform, Elowitz was able to follow the stem-cell changes over the entire surface of the device.

"It radically reconceives the whole idea of what a light microscope is," says Elowitz, a professor of biology and bioengineering at Caltech and a Howard Hughes Medical Institute investigator. "Instead of a large, heavy instrument full of delicate lenses, Yang and his team have invented a compact lightweight microscope with no lens at all, yet one that can still produce high-resolution images of living cells. Not only that, it can do so dynamically, following events over time in live cells, and across a wide range of spatial scales from the subcellular to the macroscopic."

Elowitz says the technology can capture things that would otherwise be difficult or impossible—even with state-of-the-art light microscopes that are both much more complicated and much more expensive.

"With ePetri, you can survey the entire field at once, but still maintain the ability to 'zoom in' to any cells of interest," he says. "In this regard, perhaps it's a bit like an episode of CSI where they zoom in on what would otherwise be unresolvable details in a photograph."  

Yang and his team believe the ePetri system is likely to open up a whole range of new approaches to many other biological systems as well. Since it is a platform technology, it can be applied to other devices. For example, ePetri could provide microscopy-imaging capabilities for other portable diagnostic lab-on-a-chip tools. The team is also working to build a self-contained system that would include its own small incubator. This advance would make the system more useful as a desktop diagnostic tool that could be housed in a doctor's office, reducing the need to send bacteria samples out to a lab for testing.

Seung Ah Lee, a graduate student in electrical engineering, and Yaron Antebi, a postdoctoral scholar in biology—both from Caltech—were also coauthors on the study, which is titled "The ePetri dish, an on-chip cell imaging platform based on subpixel perspective sweeping microscopy (SPSM)." Funding support was provided by the Coulter Foundation.

Written by Katie Neith

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Caltech Neuroscientists Record Novel Responses to Faces from Single Neurons in Humans

Finding offers new insights into neural basis of social perception

PASADENA, Calif.—Responding to faces is a critical tool for social interactions between humans. Without the ability to read faces and their expressions, it would be hard to tell friends from strangers upon first glance, let alone a sad person from a happy one. Now, neuroscientists from the California Institute of Technology (Caltech), with the help of collaborators at Huntington Memorial Hospital in Pasadena and Cedars-Sinai Medical Center in Los Angeles, have discovered a novel response to human faces by looking at recordings from brain cells in neurosurgical patients.

The finding, described in the journal Current Biology, provides the first description of neurons that respond strongly when the patient sees an entire face, but respond much less to a face in which only a very small region has been erased.

"The finding really surprised us," says Ueli Rutishauser, first author on the paper, a former postdoctoral fellow at Caltech, and now a visitor in the Division of Biology. "Here you have neurons that respond well to seeing pictures of whole faces, but when you show them only parts of faces, they actually respond less and less the more of the face you show. That just seems counterintuitive."

The neurons are located in a brain region called the amygdala, which has long been known to be important for the processing of emotions. However, the study results strengthen a growing belief among researchers that the amygdala has also a more general role in the processing of, and learning about, social stimuli such as faces.

Other researchers have described the amygdala's neuronal response to faces before, but this dramatic selectivity—which requires the face to be whole in order to elicit a response—is a new insight. 

"Our interpretation of this initially puzzling effect is that the brain cares about representing the entire face, and needs to be highly sensitive to anything wrong with the face, like a part missing," explains Ralph Adolphs, senior author on the study and Bren Professor of Psychology and Neuroscience and professor of biology at Caltech. "This is probably an important mechanism to ensure that we do not mistake one person for another and to help us keep track of many individuals."

The team recorded brain-cell responses in human participants who were awaiting surgery for drug-resistant epileptic seizures. As part of the preparation for surgery, the patients had electrodes implanted in their medial temporal lobes, the area of the brain where the amygdala is located. By using special clinical electrodes that have very small wires inserted, the researchers were able to observe the firings of individual neurons as participants looked at images of whole faces and partially revealed faces. The voluntary participants provided the researchers with a unique and very rare opportunity to measure responses from single neurons through the implanted depth electrodes, says Rutishauser.  

"This is really a dream collaboration for basic research scientists," he says. "At Caltech, we are very fortunate to have several nearby hospitals at which the neurosurgeons are interested in such collaborative medical research." 

The team plans to continue their studies by looking at how the same neurons respond to emotional stimuli. This future work, combined with the present study results, could be highly valuable for understanding a variety of psychiatric diseases in which this region of the brain is thought to function abnormally, such as mood disorders and autism.

Other Caltech authors on the paper are Oana Tudusciuc, a postdoctoral scholar in neuroscience and psychology, and Dirk Neumann, visiting associate in biology. Medical collaborators on the study include Adam Mamelak, a neurosurgeon at Cedars-Sinai; and Huntington Memorial Hospital's Christopher Heller, neurosurgeon; Ian Ross, neurosurgeon; Linda Philpott, neuropsychologist; and William Sutherling, medical director of the Epilepsy and Brain Mapping Program. The work in the paper "Neuronal responses selective for whole faces in the human amygdala," was supported by the National Science Foundation, the Pfeiffer Family Foundation, and the Gordon and Betty Moore Foundation.

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Four Caltech Researchers Given NIH Director's Awards

Research projects will explore membrane proteins, brain activity, genetic programming, and signaling molecules

PASADENA, Calif.—Four members of the California Institute of Technology (Caltech) faculty have been named among the researchers being given National Institutes of Health (NIH) Director's Awards. The awards are administered through the NIH's Common Fund, which provides support for research deemed to be both innovative and risky.

"The NIH Director's Award programs reinvigorate the biomedical work force by providing unique opportunities to provide research that is neither incremental nor conventional," said James M. Anderson, director of the Division of Program Coordination, Planning,  and Strategic Initiatives, which guides the Common Fund's High-Risk Research program. "The awards are intended to catalyze giant leaps forward for any area of biomedical research, allowing investigators to go in entirely new directions."

There are three types of NIH Director's Awards: the Pioneer Award, the New Innovator Award, and the Transformative Research Projects Award. This year, Caltech scientists were given two of 13 Pioneer Awards; two other Caltech researchers were among the 49 scientists given New Innovator Awards.

NIH Pioneer Awards

William Clemons Jr., assistant professor of biochemistry, and Thanos Siapas, professor of computation and neural systems, were each presented with an NIH Pioneer Award to promote what the Institutes call "pioneering and possibly transforming approaches" to key challenges in biomedical and behavioral research. 

Clemons' project will focus on membrane proteins. "Membrane proteins are an abundant and important class of molecules that play critical roles in medicine," he says. "But progress in understanding these molecules has been hindered by an inability to obtain them in significant quantities. Our goal is to examine the biological principles that cause these limitations, and discover new methods to overcome them. This award will allow us to explore these ideas in ways that aren't possible through traditional funding methods." 

Clemons received his BS from Virginia Tech in 1995, and his PhD from the University of Utah in 2000, spending time at the Laboratory of Molecular Biology in Cambridge, UK. After a postdoctoral fellowship at Harvard Medical School, he arrived at Caltech in 2005.

Siapas will use his Pioneer Award to develop neural probes for large-scale recordings of brain activity. "Brain functions such as perception, learning, and memory arise from the coordinated activation of billions of neurons distributed throughout the brain," Siapas says. "While we know a lot about the properties of individual neurons, much less is known about how assemblies of neurons interact to perform computations. Our goal is to develop large-scale, multielectrode arrays that will enable the monitoring of many neurons simultaneously across different brain areas. We hope that such arrays will expose new fundamental insights into brain activity, and will find application in the study of animal models of brain disorders."

Siapas received his BS, MS, and PhD degrees from the Massachusetts Institute of Technology in 1990, 1992, and 1996, respectively. He came to Caltech in 2002, and was named a full professor in 2010.

NIH New Innovator Awards

Long Cai, assistant professor of chemistry, and Lea Goentoro, assistant professor of biology, were each given the New Innovator Award, which the NIH says is meant to both stimulate highly innovative research and support promising new investigators.

Cai and his colleagues are working to use single-molecule microscopy to help them better understand the genetic programs in individual cells. "Our idea is to label the molecules individually," says Cai. "Then we can identify where these molecules are in the cell and how many of them are there, by single-molecule counting. "

"The goal is to monitor individual cells to find out how they work," he adds. "This may provide valuable information about rogue cells that are involved in cancer and other diseases."

Cai received his BA and PhD from Harvard in 2001 and 2006, respectively, and joined the Caltech faculty in 2010.

Goentoro will be exploring the ways in which cellular signaling molecules respond to their environment. "Have you ever noticed how we can easily whisper to each other in a quiet room, but we have to shout if we're standing on a busy road?" she asks. "In perceiving the world, our sensory systems automatically change their detection sensitivity according to the ambient condition, a phenomenon known as Weber's Law. We have found evidence to suggest that each cell in our body uses this same principle in perceiving signaling molecules in its surroundings. We will use the Innovator Award to explore this relative perception in cells, the underlying mechanism, and how it goes wrong in diseases."

"I am very grateful for the award," Goentoro adds. "It will give us precious freedom to explore ideas we are very curious about."

Goentoro's BS was awarded by the University of Wisconsin, Madison, in 2001, and she got her PhD from Princeton University in 2006. She has been at Caltech since July of this year.

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Capturing Snapshots in Time to Pick Apart Synaptic Activity

As we take in the world around us, learn, and form memories, the synapses between neurons in our brains are constantly being modified. Some get stronger, while others are allowed to shrink or get weaker. The network of enzyme-regulated chemical reactions that control these modifications is complex, to say the least. Now Mary Kennedy, the Allen and Lenabelle Davis Professor of Biology at Caltech, has come up with a way to tease apart the elusive details of that network. 

Beyond the basic scientific importance of understanding the ins and outs of our brains, the work could have significant implications for the mental health field. "It's becoming increasingly clear that slight mutations in some of these pathways make people more vulnerable to many disorders, including schizophrenia, bipolar disorder, and autism," Kennedy says.

Over the past 30 years, researchers have pieced together an understanding of the regulatory pathways and enzymes involved in controlling and modifying synaptic activity, and they've created "cartoons"—maps showing how the various components of the pathways interact. Looking at the cartoons, with their tangles of crisscrossing arrows connecting proteins and enzymes, the complexity of the network becomes apparent. 

Researchers have worked out many of the players involved and how they can interact to modify synapse strength. But they still know little about the dynamics of the network and how the processes are activated over time and under different circumstances. "We know how little strings of enzymatic processes can get activated," Kennedy says. "But we don't have very good ways of asking what happens when, say, 20 of these processes are interacting and you tweak one or two."

Now Kennedy believes she's found a way to ask such questions. The key is to stop the action in a series of samples and to see what changes from one second to the next. 

Kennedy is putting together an experimental method that will enable her to capture such "snapshots in time." She recently acquired a plunge-freeze device that she plans to modify so that it can freeze brain tissue samples in liquid propane/ethane as quickly as one second after electrical stimulation. Previously, Kennedy says, “we had no way of putting recording-electrodes into a brain slice, stimulating, and then freezing it solid or stopping it within a second.” 

There really was no reason to do so until the science and technology had progressed to a level that would enable a full analysis of the frozen samples. Kennedy says now is the time to move forward with these studies. Once she has the frozen tissue samples in hand, she'll process them with a new proteomic technique. Then, with the help of the Proteome Exploration Laboratory in the Beckman Institute, she'll be able to inject the sample into a mass spectrometer for analysis.

Many of the enzyme-driven reactions that take place in the synapses involve adding a highly energetic phosphate group to an amino acid, a process called phosphorylation, which alters the function of a protein. Since scientists have already determined the sequences of amino acids surrounding many of the critical sites of regulation in these pathways, Kennedy believes she will be able to use a mass spectrometer to measure the concentration of as many as 20 to 40 known phosphorylated sites in a single small tissue sample.

"That will let us map out the changes that happen in this large network immediately after a synchronized synaptic input," Kennedy says. "That means we'll be able to measure much more globally how these complex pathways interact with each other—which ones are more important at early stages, and which ones come in later—all of which has been very difficult to understand."

She hopes that she'll be able to use her new method to identify synaptic pathways that may be relevant to mental illnesses and Alzheimer's disease. "In order to screen in a more effective way for drugs or anything that could bring a particular set of processes into range, such global measurements are really critical," she says.

Kennedy's new Leica plunge-freeze apparatus was a gift from the Allen and Lenabelle Davis Foundation. The work is also supported by a grant from the National Institute of Mental Health. 

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Captivated by Critters: Humans Are Wired to Respond to Animals

PASADENA, Calif.—Some people feel compelled to pet every furry animal they see on the street, while others jump at the mere sight of a shark or snake on the television screen. No matter what your response is to animals, it may be thanks to a specific part of your brain that is hardwired to rapidly detect creatures of the nonhuman kind. In fact, researchers from the California Institute of Technology (Caltech) and UCLA report that neurons throughout the amygdala—a center in the brain known for processing emotional reactions—respond preferentially to images of animals.

Their findings were described in a study published online in the journal Nature Neuroscience.

The collaborative research team was responsible for recruiting 41 epilepsy patients at the Ronald Reagan UCLA Medical Center; these patients were already being monitored for brain activity related to seizures. Using electrodes already in place, the team recorded single-neuron responses in the amygdala as study participants viewed images of people, animals, landmarks, or objects. The amygdalae are two almond-shaped clusters of neurons—cells that are core components of the nervous system—located deep in the medial temporal lobe of the brain.  

"Our study shows that neurons in the human amygdala respond preferentially to pictures of animals, meaning that we saw the most amount of activity in cells when the patients looked at cats or snakes versus buildings or people," says Florian Mormann, lead author on the paper and a former postdoctoral scholar in the Division of Biology at Caltech. "This preference extends to cute as well as ugly or dangerous animals and appears to be independent of the emotional contents of the pictures. Remarkably, we find this response behavior only in the right and not in the left amygdala."

Mormann says this striking hemispheric asymmetry helps strengthen previous findings supporting the idea that, early on in vertebrate evolution, the right hemisphere became specialized in dealing with unexpected and biologically relevant stimuli, or with changes in the environment. "In terms of brain evolution, the amygdala is a very old structure, and throughout our biological history, animals—which could represent either predators or prey—were a highly relevant class of stimuli," he says. 

"This is a pretty novel finding, since most amygdala research in the past was usually about faces of people and emotions related to fear rather than pictures of animals," adds Ralph Adolphs, a coauthor on the paper and Bren Professor of Psychology and Neuroscience and professor of biology at Caltech. "Nobody would have guessed that cells in the amygdala respond more to animals than they do to human faces, and in particular that they respond to all kinds of animals, not just dangerous ones. I think this will stimulate more research and has the potential to help us better understand phobias of animals."

The study is also a clear illustration of how scientists doing basic research can benefit from working with collaborators in a clinical setting and vice versa.

"This is a good example of how special situations in neurosurgery—in this case, patients who are treated in order to cure their epilepsy—can provide a unique window into the workings of the human mind," says Itzhak Fried, a UCLA neurosurgeon and a coauthor of the study.

"A category-specific response to animals in the right human amygdala" was featured online on August 28 as an advance online publication of Nature Neuroscience. The Caltech team was led by Christof Koch, Troendle Professor of Cognitive and Behavioral Biology, and included Julien Dubois, Simon Kornblith, Milica Milosavljevic, Moran Cerf, Naotsugu Tsuchiya, and Alexander Kraskov. Rodrigo Quian Quiroga and Matias Ison from the University of Leicester also contributed to the study.

The research was supported by the European Commission, the National Research Foundation of Korea, the National Institute of Neurological Disorders and Stroke, the G. Harold and Leila Y. Mathers Foundation, the Gimbel Discovery Fund, and the Dana Foundation.  

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Katie Neith
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Caltech Group Applies New Techniques and Sees Surprises in Cell Division

PASADENA, Calif.—Researchers at the California Institute of Technology (Caltech) have obtained the first high-resolution, three-dimensional images of a cell with a nucleus undergoing cell division. The observations, made using a powerful imaging technique in combination with a new method for slicing cell samples, indicate that one of the characteristic steps of mitosis is significantly different in some cells.

During mitosis, two sets of chromosomes get paired up at the center of the cell's nucleus. Then hollow rods of proteins called microtubules, which make up a cellular structure called the spindle apparatus, grab on to the chromosomes and essentially pull each set away from the center in opposite directions, so that both daughter cells end up with a full copy of the genetic material. Typically, in the cells of plants, fungi, and many animals, one or more microtubules attach to each chromosome before the spindle will separate the sets of chromosomes from each another.

But when the Caltech researchers observed this step using their new technique, what they saw was not business as usual for a dividing cell. "We've found the first clear example of a cell where there are fewer microtubules used than chromosomes," says Grant Jensen, professor of biology at Caltech and a Howard Hughes Medical Institute investigator. The group's findings appear online in Current Biology and will be published in the September 27 issue of the journal.

Jensen's group is one of just a few in the world that uses electron cryotomography (ECT) to image biological samples. Unlike traditional electron microscopy—for which samples must be dehydrated, embedded in plastic, sectioned, and stained—ECT involves plunge-freezing samples so quickly that they become trapped in a near-native state within a layer of transparent, glasslike ice. A microscope can then capture high-resolution images of the sample as it is rotated, usually one degree at a time. 

One limitation of ECT is that samples cannot be thicker than 500 nanometers—otherwise the electron beam cannot penetrate the sample sufficiently. Therefore, ECT studies have focused on small bacteria and viruses. But Jensen's group wanted to extend the technique to observe eukaryotic cells, which are typically much bigger. So they located the smallest known eukaryote, Ostreococcus tauri, and imaged it with ECT.

The next step was to observe the important process of cell division in a eukaryote. But even tiny O. tauri exceeds the 500-nanometer limit when it is undergoing mitosis, since cells are essentially twice as big as usual when they're dividing. So the researchers needed a way to cut the frozen sample into slices, a process called cryosectioning.

"In the past when people have tried this, the sections have come off sort of like snowflakes—the material has gotten crushed," Jensen says. But Caltech electron microscopy scientist Mark Ladinsky has developed a highly successful new technique for cryosectioning samples. He slices them at about -150°C, using a special machine and a diamond knife. Then he carefully removes the slices from the knife using a micromanipulator. The technique has enabled the researchers to look at slices through dividing cells in a near-native, hydrated state.

With the new imaging and sectioning techniques working together, a former postdoctoral scholar in Jensen's lab, Lu Gan, was able to make detailed observations of mitosis in O. tauri, a cell with 20 chromosomes. Contrary to expectations, Gan observed nowhere near 40 microtubules attached to the two sets of chromosomes during mitosis; instead, he found only about 10 small, incomplete microtubules. This suggests that the chromosomes may link together to form some kind of a bundle that can then be segregated all at once by a smaller number of microtubules.

Previous studies, dating back to the 1970s, claimed to have found unicellular eukaryotic cells with fewer microtubules than chromosomes. However, those cells were chemically fixed and stained—a process that can easily damage the cells—casting doubt on the claims. But with their new imaging and sectioning techniques, the Caltech researchers feel confident that they have indeed imaged such a cell.

Their success bodes well for future studies. "Our work with O. tauri shows that we might be able to get high-resolution, three-dimensional images of other eukaryotic cells, which are much larger than bacteria," Jensen says. "We've even moved on to try to image some human cells using the same process."

The group's report, "Organization of the Smallest Eukaryotic Spindle," was supported in part by a grant from the National Institutes of Health and a fellowship from the Damon Runyon Cancer Research Foundation. The ECT imaging was made possible by a gift from the Gordon and Betty Moore Foundation. 

 

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Kimm Fesenmaier
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