A Viral Cloaking Device: Caltech biologists show how Human Cytomegalovirus hides from the immune system

PASADENA, Calif.--Viruses achieve their definition of success when they can thrive without killing their host. Now, biologists Pamela Bjorkman and Zhiru Yang of the California Institute of Technology have uncovered how one such virus, prevalent in humans, evolved over time to hide from the immune system.

The human immune system and the viruses hosted by our bodies are in a continual dance for survival--viruses ever seek new ways to evade detection, and our immune system devises new methods to hunt them down. Human Cytomegalovirus (HCMV), says Bjorkman, Caltech's Delbrück Professor of Biology and a Howard Hughes Medical Institute (HHMI) Investigator, "is the definition of a successful virus--it thrives but it doesn't affect the host."

HCMV is carried by eight in 10 people. Although it generally harms only those who are immunocompromised, it has also been linked with brain tumors like the one for which Ted Kennedy recently had surgery. Understanding how HCMV survives may help in the development of a vaccine, as well as in the fight against other viruses with similar evasive tactics.

"We are interested in mechanisms taken by viruses to escape our immune system," says Caltech biology postdoc and HHMI associate Zhiru Yang. She and Bjorkman published their findings on HCMV survival mechanisms in the July 15 edition of Proceedings of the National Academy of Sciences. They describe the underpinnings of a viral cloaking device, partly made of stolen goods from healthy cells, that helps HCMV to move undetected through the body.

For 20 years, Bjorkman's lab has been dedicated to understanding class 1 major histocompatibility complex (MHC) proteins and the immune response, most recently related to AIDS research. MHC proteins carry peptides, small pieces that are chopped up from the cell's internal proteins, to the cell's surface. If a cell has been infected, MHC presents viral peptides to signal T cells to kill it. So some viruses evolved to evade T cells by keeping MHC from reaching the cell surface. In turn, the immune system recruited other hunters to search for cells that don't show MHC proteins.

Sometime along its treacherous evolutionary path, HCMV stole a class 1 MHC molecule from its host and modified it for supreme stealth. "This is a decoy," Bjorkman says. She and Yang analyzed the structure of the mimic, called UL18, to compare how similar it is to the real thing. They found that despite a mere 23 percent match in genetic sequences, UL18 looks almost exactly the same as a true class 1 MHC.

The same immune cells that search for missing MHC proteins are designed to bind to them when they find them, thereby inhibiting an immune response. Yang and Bjorkman found that UL18 happens to bind 1,000 times tighter to these inhibitory receptors than real MHC molecules do. "This is exactly what the virus wants--to avoid being recognized by T cells, but to engage inhibitory receptors to turn off immune cells," Yang notes. "Only a small number of UL18 molecules are required to have the same inhibitory effect as a large number of MHC class I molecules."

"What I find astounding is that the virus stole this gene and kept it almost identical but improved upon its binding," Bjorkman says.

UL18 didn't stop there. "It also binds peptides--that's unique to this MHC mimic. We don't know why," Bjorkman adds. The peptide is obscured from killer cells by yet another shield, Yang says. In a trait it shares with HIV proteins, HCMV's UL18 covers itself with carbohydrates, which are unrecognizable to the immune system. A real class 1 MHC molecule has one site for adding carbohydrates; the fake has 13, Bjorkman notes. The only place where it's not covered is where it binds to the inhibitory receptor.

All its efforts have made UL18 virtually undetectable. "It's a good example of a viral protein that evolved from its host ancestor to block unwanted interactions," Yang says. "The more we understand that, the more effectively we can fight viruses that hide out," Bjorkman adds.

Elisabeth Nadin

Protein Expert Joins Inaugural Class of Science Fellows:Caltech Vice Provost recognized with new Department of Defense award

PASADENA, Calif.--The Department of Defense (DoD) named California Institute of Technology Vice Provost Stephen Mayo one of six university faculty scientists and engineers in the inaugural class of National Security Science and Engineering Faculty Fellows (NSSEFF). Up to $3 million of direct research support will be given to each NSSEFF fellow for up to five years. The grants are intended to engage the next generation of outstanding scientists and engineers in the most challenging technical issues facing the DoD.

Mayo, the Bren Professor of Biology and Chemistry at Caltech, is an expert in the field of protein design. The DoD funding will support his work in developing and testing computer algorithms for designing proteins. For the NSSEFF program, he is focused on developing novel proteins, including engineered antibodies and antibody-like molecules, that could be useful in preventing and treating viral diseases, such as those caused by avian flu, smallpox, and dengue.

"I'm excited to get this support to further my research," says Mayo. "All six projects chosen by the Defense Department are in extremely diverse disciplines, and I'm thrilled to be a part of it."

William Rees, deputy undersecretary of defense for laboratories and basic sciences, says the fellows conduct basic research in core science and engineering disciplines that underpin future DoD technology development. In addition to this unclassified research, Rees noted another important benefit of the NSSEFF:

"The program provides opportunities for fellows to participate fully in the DoD research enterprise and share their knowledge and insight with DoD military and civilian leaders, researchers in DoD laboratories, and the national security science and engineering community."

Nearly 150 academic institutions submitted more than 500 nomination letters for the fellowships. Twenty semifinalists were invited to submit full proposals outlining their research plans. Each of the semifinalists participated in a scientific interview before a distinguished panel of experts. The DoD may announce additional winners of this year's NSSEFF awards at a later date.

Upon successful completion of negotiations between the fellows' academic institutions and DoD research offices, grant awards will be made to the their' home institutions for support of their research.

Jacqueline Scahill
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Caltech Scientists Decipher the Neurological Basis of Timely Movement

PASADENA, Calif--Contrary to what one might imagine, the way in which each of us interacts with the world is not a simple matter of seeing (or touching, or smelling) and then reacting. Even the best baseball hitter eyeing a fastball does not swing at what he sees. The neurons and neural connections that make up our sensory systems are far too slow for this to work. "Everything we sense is a little bit in the past," says Richard A. Andersen of the California Institute of Technology, who has now uncovered the trick the brain uses to get around this puzzling problem.

Work by Andersen, the James G. Boswell Professor of Neuroscience at Caltech, and his colleagues Grant Mulliken of MIT and Sam Musallam of McGill University, offers the first neural evidence that voluntary limb movements are guided by our brain's prediction of what will happen an instant into the future. "The brain is generating its own version of the world, a 'forward model,' which allows you to know where you actually are in real time. It takes the delays out of the system," Andersen says.

The research in Andersen's laboratory is focused on understanding the neurobiological underpinnings of brain processes, including the senses of sight, hearing, balance, and touch, and the neural mechanisms of action. The lab is working toward the development of implanted neural prosthetic devices that would serve as an interface between severely paralyzed individuals' brain signals and their artificial limbs--allowing thoughts to control movement.

Research along these lines conducted at the University of Pittsburgh and Carnegie Mellon University recently allowed monkeys to feed themselves using a robotic limb that they controlled only with their thoughts. Their thoughts were picked up via an array of electrodes sitting on top of the primary motor cortex, a lower level brain region responsible for carrying out motor functions.

Andersen's group focuses on a more high-level area of cortex called the posterior parietal cortex (PPC), which is where sensory stimuli are actually transformed into movement plans.

In their experiments, Andersen and his colleagues trained two monkeys to use a joystick to move a cursor on a computer screen from a small red circle into a green circle, while keeping their gaze fixed on the red circle. The monkeys typically generated curved trajectories, but to increase the curvature one monkey was trained to move the cursor around an obstacle. The obstacle (a large blue circle) was placed between the initial location of the cursor and the target circle, and the monkey had to guide the cursor around the obstacle, without touching it, and over to the green circle. As the monkeys conducted the tasks, electrodes measured the activity of neurons in the PPC. This allowed Andersen and his colleagues to monitor signals--commands for movement--in real time.

The studies showed that neurons in the PPC produce signals that represent the brain's estimation of the current and upcoming movement of the cursor. "An internal estimate of the current state of the cursor can be used immediately by the brain to rapidly correct a movement, avoiding having to rely entirely on late-arriving sensory information, which can result in slow and unstable control," Mulliken says.

"The idea is that you feed back the command you make for movement into those areas of the brain that plan the movement (i.e., the PPC)," Andersen says. "The signal about the movement taking place is adjusted to be perfectly aligned in time with the actual movement--what you're moving in your head matches with what you're moving in the real world." The effect is akin to an athlete visualizing his performance in his mind. Studies have previously shown that these simulations of movement trajectories run through the posterior parietal cortex, and run at actual speed, taking the same amount of time as the activity would in real life.

In the Pittsburgh robotic arm study, the neural signal driving the robotic limb was what is known as a "trajectory signal," which represents the path that must be taken to move from one point to another, like using a computer mouse to drag an object across a screen. Previously Andersen's lab had shown that a different signal in the posterior parietal cortex, called the "goal signal," can also be used to directly jump an object from one point to another.

"This goal signal is much faster for reaching a goal than a trajectory signal," Andersen says. "Fast goal decoding is very advantageous for rapid sequences such as typing. Our new study shows that the posterior parietal cortex codes the trajectory as well as the goal, which makes this brain area an attractive target for neural prosthesis. Not only does this increase the versatility and the number of prosthetic applications, but it also makes the decoding easier since the trajectories can be better estimated if the goal is known."

The paper, "Forward Estimation of Movement State in Posterior Parietal Cortex," will be published in a future print issue the Proceedings of the National Academy of Sciences but is now available online. First author, Grant Mulliken, was a graduate student at Caltech and is now a postdoctoral fellow at the Massachusetts Institute of Technology; coauthor Sam Musallam was a postdoctoral fellow at Caltech and is currently an assistant professor at McGill University in Montreal, Canada.

Kathy Svitil
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Getting Better with a Little Help from Our "Micro" Friends

PASADENA, Calif.-- A naturally occurring molecule made by symbiotic gut bacteria may offer a new type of treatment for inflammatory bowel disease, according to scientists at the California Institute of Technology.

"Most people tend to think of bacteria as insidious organisms that only make us sick," says Sarkis K. Mazmanian, an assistant professor of biology at Caltech, whose laboratory examines the symbiotic relationship between "good" bacteria and their mammalian hosts. Instead, he says, "bacteria can be beneficial and actively promote health."

For example, the 100 trillion bacteria occupying the human gut have evolved along with the human digestive and immune systems for millions of years. Some harmful microbes are responsible for infection and acute disease, while "other bacteria, the more intelligent ones, have taken the evolutionary route of shaping their environment by positively interacting with the host immune system to promote health, which gives them an improved place to live; it's like creating bacterial nirvana," says Mazmanian.

If bacteria are actively modifying the gut, their work would have to be mediated by molecules. In their recent work, Mazmanian and his colleagues have identified one such molecule, a sugar called polysaccharide A, or PSA, which is produced by the symbiotic gut bacterium Bacteroides fragilis. They have termed this molecule a "symbiosis factor," and predict that many other bacterial compounds with diverse beneficial activities await discovery.

To identify the molecule and its action, the collaborative team, which included Dennis L. Kasper, Professor of Microbiology and Molecular Genetics at Harvard Medical School, used experimental mice and induced changes to their intestinal bacteria by exposing them to a pathogenic bacterium called Helicobacter hepaticus. This microbe causes a disease in the mice that is similar to Crohn's disease and ulcerative colitis. However, when the animals were co-colonized with B. fragilis, they were protected from the disease--as were animals that were given oral doses of just the PSA molecule.

In particular, Mazmanian and his colleagues found that PSA induced particular immune-system cells called CD4+ T cells to produce interleukin-10 (IL-10), a molecule that has previously been shown to suppress inflammation--and offer protection from inflammatory bowel disease. "Thus, bacteria help reprogram our own immune system to promote health," he says.

"The most immediate and obvious implication is that PSA may potentially be developed as a natural therapeutic for inflammatory bowel disease," says Mazmanian.

Inflammatory bowel disease, a constellation of illnesses that cause inflammation in the intestines, including ulcerative colitis and Crohn's disease, is estimated to affect one million Americans. The rates of inflammatory bowel diseases have skyrocketed in recent years; for example, the incidence of Crohn's disease, a condition that causes debilitating pain, diarrhea, and other gastrointestinal symptoms, has increased by 400 percent over the past 20 years.

The current research, along with other work by Mazmanian and June L. Round, a Caltech postdoctoral researcher, suggests that the interplay between various groups of bacteria living in the intestines has profound effects on human health.

This notion gels with the so-called "hygiene hypothesis." The hypothesis, first proposed two decades ago, links modern practices like sanitation, vaccination, a Western diet, and antibiotic use, which reduce bacterial infections, to the increased prevalence of a variety of illnesses in the developed world, including inflammatory bowel disease, asthma, multiple sclerosis, and Type 1 diabetes. However, it is now clear that increased living standards and antibacterial drugs affect not only infectious microbes, but all of the beneficial ones that we may depend on for our well-being.

"Through societal measures we have changed our association with the microbial world in a very short time span. We don't have the same contact with microbes as we have for millions of years--we just live too clean now," Mazmanian says. So while it is useful to eliminate disease-causing organisms, "perhaps disease results from the absence of beneficial bacteria and their good effects," he suggests. "This study is the first demonstration of that. What it hopefully will do is allow people to re-evaluate our opinions of bacteria. Not all are bad and some, maybe many, are beneficial."

The article, "A microbial symbiosis factor prevents intestinal inflammatory disease," will be featured on the cover of the May 29 issue of the journal Nature. Mazmanian's coauthors are June L. Round of Caltech and Dennis L. Kasper of Harvard Medical School. 

Kathy Svitil

Sight Recovery After Blindness Offers New Insights on Brain Reorganization

PASADENA, Calif.--Studies of the brains of blind persons whose sight was partially restored later in life have produced a compelling example of the brain's ability to adapt to new circumstances and rewire and reconfigure itself.

The research, conducted by postdoctoral researcher Melissa Saenz of the California Institute of Technology along with Christof Koch, the Lois and Victor Troendle Professor of Cognitive and Behavioral Biology and professor of computation and neural systems, and their colleagues, shows that the part of the brain that processes visual information in normal individuals can be co-opted to respond to both visual and auditory information. That brain reorganization persists even if the blind subjects later regain their vision--for example, through technologies such as corneal stem-cell transplants, retinal prosthetics, and gene therapy.

"Sight-recovery patients can face many challenges in using restored vision because of brain reorganization that occurs during prolonged blindness. Understanding this brain adaptation will be useful for helping patients make the best use of their restored vision," says Saenz.

Researchers scanned the brains of two individuals whose sight had been recovered decades after having been lost. One volunteer, Michael May, was blinded in a chemical accident at the age of three, and then he had his vision partially restored in his left eye at age 46 through a corneal stem-cell transplant. The second subject, a 53-year-old woman, had been blind since birth because of damage to the retina and cataracts. At age 43, sight in her right eye was partially restored by cataract removal.

Each subject listened through headphones to several types of sounds including speech, frequency sweeps (simple tones whose frequency changes), and sounds that appeared to be "moving" horizontally from one side of the head to the other (the illusion was created by increasing the volume or timing of sounds delivered to either the left or the right speaker) while lying in a magnetic scanner.

This allowed Saenz to monitor changes in blood flow that are closely linked to the underlying neuronal activity in a region of the brain called MT+/V5, which is specifically involved in visual motion processing. Ten test subjects with normal vision were similarly studied.

Only in the two individuals with recovered sight did the MT+/V5 region light up in response to sound. No response was seen in the control subjects.

"Previous studies had shown that a variety of new sensory functions move into the visual cortex when a person loses their vision, especially when vision is lost as a young child, when the brain is very adaptable," says Saenz. "Our data show for the first time what happens to the new sensory responses if a blind person has the chance to see again. The sound responses didn't go away. They persisted together with the restored visual responses, even after many years with regained sight."

Most interestingly, the MT+/V5 region reacted only to auditory motion, but not to other types of auditory stimuli. In other words, moving sound activated a part of the brain that is normally reserved for processing moving visual images.

"This wasn't a random takeover. We didn't find responses to all types of sounds, but specifically to moving sounds. This brain reorganization was efficient and took advantage of this region's specialized role in motion processing," she says.

"Our volunteers with sight recovery gave us the unique opportunity to answer the question of whether the different sensory response in a blind person activates a specific visual area (MT+/V5). Normally, the location of this area is variable and is identified in sighted people by how it responds to visual stimulation, not based on anatomical landmarks alone. So we couldn't convince a critic that we identified this area in someone who was still blind."

In fact, According to Saenz, such multitasking may contribute to the strong ability to perceive motion--as opposed to the poor visual acuity--that has been seen before among patients who have recovered their sight after a lifetime of blindness.

"This study demonstrates the plasticity inherent in even adult brains and the very tight linkage between neural activity in particular pieces of gray matter and the subject's perception in the privacy of his and her mind," Koch says.

"When my vision was restored after 43 years of being totally blind, I had no idea of the complexity of how our brain sees," says test subject Michael May. "It is through vision scientists that I have had a front-row seat in learning about how I perceive the world with my new vision. Turns out that the integration of all my senses, tools, and techniques has been the key to a maximum life experience."

The paper, "Visual motion area MT+/V5 responds to auditory motion in human sight-recovery subjects," was published in the May 14 issue of the Journal of Neuroscience.

Go to http://www.klab.caltech.edu/~saenz/soundstimuli.html for samples of the auditory stimuli.

Kathy Svitil
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Illusions of the Present

PASADENA, Calif.--Have you ever noticed that signposts and trees on the side of the road seem to whoosh by faster right as you drive past them, or that a door frame seems to curve outward as you approach it? These are just two examples of real-life movements that underlie more than 50 types of illusions, now systematically organized and explained by scientists at the California Institute of Technology.

The systematization also lends a glimpse into how illusions are not simply tricks your brain likes to play on you; they are manifestations of how the visual system evolved to keep up with real-life motion. These illusions now fall into 28 predictable categories defined by Mark Changizi during a fellowship in the Sloan-Swartz Center for Theoretical Neurobiology at Caltech and appearing May 28 in the journal Cognitive Science.

"I had been reflecting on the classical geometrical illusions always shown in Psychology 101 classes--the ones involving lines and vanishing points--and it struck me that I can explain them," Changizi says.

To picture a geometrical illusion, imagine a spoked bike wheel with two squares superimposed on it in different places. The square closer to the center, where the spokes meet--called the vanishing point--will always seem larger than the square toward the rim of the wheel. In other words, the closer an object is to the vanishing point, the larger it appears.

Your brain thinks that you are physically moving forward. In real life, forward motion would generate "spokes" on the eye's retina, "like in Star Trek, when they go into warp speed," Changizi describes. It would also bring you closer to that square near the wheel's center, naturally making it seem larger than the other object. "Your brain generates a perception of what the world will be like in the next moment because by the time that perception finally occurs--it takes about a tenth of a second--that object will be larger," explains Changizi.

"Later I realized that my same old idea could be radically generalized, so that it made predictions not just about geometrical illusions, but about 27 other illusion classes as well," Changizi says. "I realized that I could make a massive pattern of predictions about the kinds of illusions humans are subject to."

Changizi built a table, a matrix that distributes the different kinds of illusions into four columns distinguishing what visual feature is misperceived (size, speed, luminance, and distance), and seven rows indicating the different kinds of optical features that occur when an observer is moving forward. "Each spot in this table makes a prediction about perception," he says.

From there, Changizi culled a century's worth of papers reporting what people see when they look at different kinds of illusions. "There are hundreds of illusions collected like butterflies over the years," he notes, "with no real systematics behind them. Just a massive heap of illusions." He wanted to see if each individual case would fall into one of the 28 classes he had designated. "I found that the disordered pile of illusions followed the predicted pattern, and I was able to arrange the illusions in an orderly fashion inside the unifying matrix."

Changizi believes these illusions arise from the way the visual system evolved to process and react to visual cues. Called "perceiving the present," the theory explains, for example, why your hand is ready to hit the ball in a game of tennis: your brain translates the ball's motion into where it will be when you hit it.

"Motion is crucial to the story of illusions. What you perceive is a premonition, not present reality!" Changizi notes. Shinsuke Shimojo, a biology professor at Caltech and a coauthor on the report, explains, "We have evidence from other studies showing that when you perceive a moving object, you localize it in the current position because your brain normalizes it. The brain has been trained via genetic and learning processes to compensate in dynamic situations. This paper says even more--that the brain applies the same algorithm to perceive a static image. Nobody had come up with this theory to explain all illusions in this framework."

The potential applications that the new organization of illusions presents are dizzying. Movies or video games, for example, could incorporate illusions to "make someone perceive motion when the object is actually motionless," Changizi suggests. Another possibility: street signs or other visual warnings could incorporate visual tricks to grab attention, by having a pattern that seems to bulge, spiral, or turn redder as the viewer approaches.

Changizi is now an assistant professor of cognitive science at Rensselaer Polytechnic Institute. Other authors on the study are Andrew Hsieh, a former Caltech undergraduate student now at the University of Southern California; Romi Nijhawan, a psychologist at the University of Sussex in England; and Ryota Kanai, a former postdoc in Shimojo's lab now at the Institute of Cognitive Neuroscience in London. 

Elisabeth Nadin

Unraveling the Genomic Code for Development

PASADENA, Calif.-- Scientists at the California Institute of Technology have produced the first complete description of the complex network of genes that create a particular type of cell in an organism.

Scientists have known for decades that the program for development is encoded in the genome, the total genetic complement of any living thing. "Cats beget cats and frogs beget frogs, so how you develop depends on what genome you've inherited," says Eric H. Davidson, the Norman Chandler Professor of Cell Biology at Caltech.

Just knowing the sequence of the genome, however, won't get you far. To actually make a cat or a frog, you need to understand the relationships between genes--what genes control other genes, turning them on or off at specific times during the development of the organism to produce an organism's skeletal system, or leaves, or skin. Biologists call the complex network of gene interactions involved in this process a gene regulatory network.

In 2006, the Baylor College of Medicine Human Genome Sequencing Center, along with Davidson and Andy Cameron of Caltech, and an international team of researchers from more than 70 institutions, revealed the entire 814 million base-pair sequence of the genome of the California purple sea urchin (Strongylocentrotus purpuratus). The genome is about one-fourth the size of the human genome, and contains some 23,300 genes.

Using these data and other techniques to determine the regulatory genes expressed at each point during embryonic development and how their interrelationships influence the architecture of the sea urchin's skeletal system, Davidson and his colleagues created a complete blueprint for the development of a lineage of cells whose particular function is to build a series of biomineral skeletal rods inside the embryo.

The work, coauthored by Qiang Tu, a postdoctoral research fellow at Caltech, and Paola Oliveri, now of University College London, appears in the April 22 issue of the Proceedings of the National Academy of Sciences.

Unlike a regular blueprint, which describes how to simultaneously construct all of the various parts of a structure, the gene regulatory network represents a dynamically changing plan, with the relationships between genes at one stage providing the program for the next stage of development.

According to Davidson, the research marks the first time that all of the "moving parts"--the regulatory genes specifically expressed in a particular developmental process that recognize target DNA sequences, bind them, and control the expression of other genes--have been included in a gene regulatory network.

"We've reached the point where all of the biology that you see in a microscope for this cell lineage can be interpreted in terms of what we know about this control program. The network concerns only one day in the life cycle of an animal that lives for 50 or a hundred years, and only one cell lineage of the embryo, but it is a step forward to be able to relate the biology to the regulatory DNA sequence in this way."

In a commentary accompanying the published paper, biologist Leroy Hood of the Institute for Systems Biology describes the study as a "tour de force." The research, he says, "represents a brilliant integration of biology, technology, computational approaches, and powerful logic." The paper, he adds, "will be the model for many more that will undoubtedly follow, transforming the landscape of developmental biology and ultimately elucidating the molecular systems that drive development."

The major effort in the Davidson lab is to decipher the gene regulatory networks that control the rest of the embryonic development of the California purple sea urchin.

That information will reveal for the first time the code for a whole embryo, a small but complex creature. At that point, scientists can begin to tinker with and re-engineer the network--a process that simulates the genetic changes that accompany the evolution of organisms in real life. "The evolution of animals is due to changes in the structure of these gene regulatory networks, so this work provides us with an opportunity to study evolution in a new and decisive way," he says.

Indeed, in a second paper in the same issue of the journal, Davidson and his colleague Feng Gao report that the gene regulatory network for the sea urchin's embryonic skeletal development evolved from another network present in adult animals, and probably was co-opted into the embryonic network by hijacking a big piece of the regulatory apparatus that controls the construction of the adult skeletal system. 

Kathy Svitil
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Two Faculty Members Join American Academy of Arts and Sciences

PASADENA, Calif.--Caltech professors Michael Dickinson and Thomas Palfrey are among the 190 new fellows elected to the American Academy of Arts and Sciences this year. They join an assembly that was founded in 1780 by John Adams, James Bowdoin, John Hancock, and other scholars to provide practical solutions to pressing issues.

Their election brings the Caltech total membership to 86.

Thomas Palfrey, Caltech's Flintridge Foundation Professor of Economics and Political Science and also a Caltech grad (PhD '81), specializes in the study of voting and elections, economic and political theory, public and experimental economics, and game theory.

A central focus of Palfrey's research is how people devise strategies when faced with incomplete information. He has applied game theory to examine voting behavior in committees and elections, and bidding in auctions. He founded or cofounded several experimental labs, including the California Social Science Experimental Laboratory at UCLA, the Social Science Experimental Laboratory at Caltech, and the Princeton Social Science Experimental Laboratory, and used observations from experiments to help develop a general theory of strategic behavior with human error. Called Quantal Response Equilibrium, it has been successfully applied to study a broad range of political and economic behavior.

Michael Dickinson, the Zarem Professor of Bioengineering at Caltech, studies animal physiology and behavior. He has become well known for Robofly, a mechanical fly that sprang from his work on the neurobiology and biomechanics of fly locomotion. Throughout his career, Dickinson has used a variety of tools, such as wind tunnels, virtual reality simulators, high-speed video, and giant robotic models, to determine how the poppy seed-sized brains of these tiny insects can rapidly control aerodynamic forces.

More than a simple understanding of the material basis for insect flight, Dickinson's studies provide insight into complex systems operating on biological and physical principles: neuronal signaling within brains, the dynamics of unsteady fluid flow, the structural mechanics of composite materials, and the behavior of nonlinear systems are all linked when a fly takes wing.

"The Academy honors excellence by electing to membership remarkable men and women who have made preeminent contributions to their fields, and to the world," says Academy president Emilio Bizzi. "We are pleased to welcome into the Academy these new members to help advance our founders' goal of 'cherishing knowledge and shaping the future.'" An independent policy research center, the Academy currently focuses on science, technology, and global security; social policy and American institutions; the humanities and culture; and education.

Dickinson and Palfrey will be inducted into the Academy at a ceremony on October 11, at the organization's headquarters in Cambridge, Massachusetts.

Other new members include legendary blues guitarist B. B. King, two-time cabinet secretary and former White House Chief of Staff James Baker III, and former eBay CEO Margaret Whitman, as well as foreign honorary member Pedro Almodóvar, a Spanish film director. 

Elisabeth Nadin
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Decoupling through Synchrony

PASADENA, Calif-In the brain, as in sports, sex, and life, timing--and teamwork--are everything. Such is the message of a series of studies by researchers at the California Institute of Technology that offer insight into the processes by which memories are stored in the brain and that may someday guide the development of new therapies to prevent epileptic seizures.

Using computer models of neuronal circuits and experiments on live rats, Athanassios Siapas, assistant professor of computation and neural systems at Caltech, and his postdoctoral researcher Evgueniy Lubenov are revealing the curious mechanism by which the brain spontaneously tips itself toward a state balanced between order and chaos. The driving factor in the brain's self-regulation, they say, is the timing of neural pulses.

The researchers looked at how the timing of pulses fired by neurons in a simulated network (and, later, within the brains of freely roaming rats) interact with the plasticity in the synaptic connections between those neurons to influence the system as a whole. The studies revealed that when neurons fire in synchronized bursts, their harmony is fleeting; over time, the very act of synchrony tends to decouple the neurons, so that they become less organized, and their subsequent firing patterns more random.

Conversely, when neurons initially fire in a more random pattern, the randomness leads to strengthening of connections that drive the system toward a more synchronized firing pattern.

"Networks self-organize to an intermediate state, in between the two extremes," Siapas says.

Beyond its relevance to a basic understanding of neuronal circuits, the study may also prove significant for other, more clinically important, research. For example, overly synchronized neuronal firing is a characteristic of seizures in patients with epilepsy. Researchers have recently begun studying the effectiveness of deep brain stimulation in epilepsy patients. In the procedure, a device called a brain pacemaker is inserted into the brain, where it delivers electrical pulses to targeted regions.

"If this stimulation translates into the generation of synchronous events, it could decouple a possible locus for synchronous activity, while guiding the selection of targets for deep brain stimulation," thus reducing seizures, says Siapas. "One can fight synchrony with synchrony," he says, although he stresses that this is merely a conjecture and not based in experimental evidence.

The research also points to a mechanism by which short-term memories could be transferred from the hippocampus, a brain region involved in memory formation, to the neocortex, the area where long-term memories are held.

Neuroscientists have long known that during slow-wave sleep, the hippocampus exhibits a surge in synchronized neural firing directed to the neocortex. "This simultaneous activity is very effective at driving cortical neurons and strengthening the interactions between them," Lubenov says, and thus consolidating that information in the neocortex. In essence, a permanent memory is formed.

"We believe those same synchronous bursts also have a consequence for the memory trace in the hippocampus itself," Lubenov says, which is related to the self-organization that he and Siapas found in the system.

Their idea is that because synchronized neural firing in the hippocampus during this information transfer acts to desynchronize the system, it would reduce the strength "and lead to the gradual weakening of the hippocampal memory trace," Siapas says. Indeed, in experiments on rats implanted with electrodes, the researchers found a reduction in the simultaneous firing of neurons over the course of slow-wave sleep, indicating a move from synchrony to asynchrony. Eventually, through this process, a memory trace--unless reinforced through experience--would be erased from the hippocampus, freeing up neural resources there that could then be used to store new memories.

The paper, "Decoupling through synchrony in neuronal circuits with propagation delays," appears in the April issue of the journal Neuron.

Kathy Svitil

Geneticist Giuseppe Attardi Dies

PASADENA, Calif.--Giuseppe Attardi, whose work linked degenerative diseases and aging to genetic mutations, died at his home in Altadena on Saturday, April 5. He was 84 years old.

Attardi, the California Institute of Technology's Steele Professor of Molecular Biology, was among the first scientists to delve into the processes through which DNA's information is transferred. He identified all the genes of the DNA in human mitochondria--often called the powerhouses of biological cells. He then developed techniques for investigating genetic diseases, including Alzheimer's, and aging in general, which he discovered is associated with changes in mitochondrial DNA (mtDNA).

Born in 1923 in Vicari, Italy, a town of less than 3,000 people in the Province of Palermo, Attardi earned an MD from the University of Padua in 1947. He remained there for almost 10 years as an assistant professor in the Institute for Histology and General Embryology. During those years, he also visited the Karolinska Institute in Stockholm, Sweden, as a research fellow in cell research and genetics, and the Washington University in St. Louis School of Medicine as a Fulbright Fellow.

Still on the Fulbright Fellowship, Attardi arrived at Caltech in 1959. He was appointed associate professor of molecular biology four years later. It was at Caltech that Attardi turned his interests to mitochondria, establishing that mtDNA is an active, working genome. This spurred research into the organelle's genetic machinery.

David Chan, an associate professor of biology and Attardi's colleague and friend, credits Attardi with being a leading figure in identifying the products and functions of the mitochondrial genome. Attardi and a student developed a technique in which they replaced the mtDNA of a human cell line with the mtDNA from diseased cells. This allowed them to distinguish the roles of mtDNA and the genome of the nucleus--where the rest of a cell's DNA resides--in causing the disease. With this technique, they could also examine the relationship between changes in mtDNA and changes in cell function caused by the disease. "Many labs have used his approach to understand how mutations in mtDNA diseases affect mitochondrial function," Chan says.

"Giuseppe was one of the founders of what is now a central and still-expanding area of molecular cell biology," adds Attardi's colleague and friend Gottfried Schatz, emeritus professor of biochemistry at the University of Basel's Biozentrum, in Switzerland. "His unique insights bore magnificent fruits with the landmark description of the transcription map of mammalian mtDNA, as well as the precise characterization of the mechanism of mitochondrial diseases and the dynamics of human mitochondrial genomes."

In recent years, researchers in Attardi's lab at Caltech have focused on how mtDNA replicates, and on detecting mutations that result from aging, and what effects those mutations have. The team discovered that older people carry a significantly greater number of genetic defects in a specific region of their mtDNA, suggesting that cell aging begins in the mitochondria.

"He has been a central figure in mitochondrial research for several decades. One of the things I will always remember about him is his constant excitement for all types of biological questions," Chan says. "I think his intense curiosity is one reason he accomplished so much as a scientist."

Schatz adds, "To him, science was everything and he never tired of discussing the latest experiments. Yet he also embodied a vanishing breed of scientists whom I would define as 'gentlemen intellectuals.' He had a superb grasp of European history and world culture, had mastered French and German at a very high level of proficiency, and even in his most spirited discussions refrained from personal invective or overt aggression. To me, he was an example of how science can keep us young in spirit, and ennoble us."

During his career, Attardi garnered several distinctions. They include two Guggenheim Fellowships; election to the National Academy of Sciences; the Antonio Feltrinelli International Prize for Medicine from the Accademia Nazionale dei Lincei; a degree of doctor honoris causa from the University of Zaragoza, Spain; the Passano Foundation Award; and the Gairdner Foundation International Prize.

Attardi is survived by his wife and fellow researcher, Anne Chomyn, a senior research associate, emeritus, at Caltech; a son, Luigi Attardi, of Rome; a daughter, Laura Attardi, of Palo Alto, who is a professor of cancer biology at Stanford University; and a grandson, Marcello Attardi, of Palo Alto.

Elisabeth Nadin
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