Caltech Scientists Find Cells Coordinate Gene Activity with FM Bursts

PASADENA, Calif.-- How a cell achieves the coordinated control of a number of genes at the same time, a process that's necessary for it to regulate its own behavior and development, has long puzzled scientists. Michael Elowitz, an assistant professor of biology and applied physics at the California Institute of Technology (Caltech), along with Long Cai, a postdoctoral research scholar at Caltech, and graduate student Chiraj Dalal, have discovered a surprising answer. Just as human engineers control devices ranging from dimmer switches to retrorockets using pulsed--or frequency modulated (FM)--signals, cells tune the expression of groups of genes using discrete bursts of activation.

Elowitz, who is also a Bren Scholar and an investigator with the Howard Hughes Medical Institute, and his colleagues discovered this process by combining mathematical and computational modeling with experiments on individual living cells. The scientists looked specifically at the molecular changes within simple baker's yeast (Saccharomyces cerevisiae) cells after exposure to excess calcium, which increases in concentration in cells in response to stressful conditions such as high salt levels, alkaline pH, and cell wall damage.

The scientists tracked that response using a protein called Crz1 labeled with a green fluorescent tag. Crz1 is stimulated in response to high calcium levels and activates genes that help protect the cell. The glowing of the fluorescent marker allowed Elowitz and colleagues to visualize the movement of Crz1 as it travelled within the cell from the cytoplasm into the cell nucleus and out again into the cytoplasm. Using time-lapse microscopy, they created "movies" of that movement.

"This allowed us to discover that the localization of the Crz1 protein was randomly switching between nucleus and cytoplasm," says Elowitz. The researchers were able to see the Crz1 protein moving in a coherent fashion. "What's striking is that most of the Crz1 molecules jump in or out of the nucleus together. The typical length of time they stay in the nucleus is constant, but how often they all jump into the nucleus depends on the signal--in this case, calcium. Thus, you can say that calcium levels are 'encoded' in the frequency of these nuclear localization bursts."

Using mathematical modeling, the researchers were then able to determine that the burst-like movement most likely serves to coordinate gene expression. The process is similar to how a dimmer switch on household lights works. Such knobs control the fraction of time that current, which switches on and off rapidly, goes to the light fixture. Rotating the knob varies the relative amount of time that current is on or off, and the resulting intensity of the light is proportional to the fraction of time the switch is on. "The idea of controlling a system by flipping it between extreme 'on' and 'off' states at different rates, rather than fine-tuning it, is sometimes called 'bang bang' regulation," Elowitz says.

"Similarly, the amount of gene expression in the Crz1 system is proportional to the fraction of time that Crz1 is localized to the nucleus. Unlike the dimmer, it is the frequency--how often there are nuclear localization pulses--not the duration of these pulses, which the cell regulates. But in both cases, it is the fraction of time that the system is 'on' that is being controlled," Elowitz says.

One key point, he adds, "is that as the rate of these jumps changes, all genes are affected in the same way. One way of thinking about it is that each 'jump' activates all of the genes, albeit at different levels. Therefore, the expression of each gene is individually proportional to the number or frequency of these jumps, and they are all proportional to each other as well."

The behavior of Crz1 is believed to control roughly 100 target genes. However, Elowitz and his colleagues suspect that frequency-modulated movement may be a common strategy for gene regulation. "Because the problem of coregulation of genes is very general, we suspect frequency modulation may be widespread across many genes, organisms, and cell types. We're now trying to determine how general this phenomenon is by looking at what other genes and cell types use this type of system," he says.

The paper, "Frequency-modulated nuclear localization bursts coordinate gene regulation," was published in the September 25 issue of the journal Nature. The work was supported by grants from the National Institutes of Health and the Packard Foundation.

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Bruce A. Hay, Caltech Biologist, Named NIH Pioneer Award Recipient

Will study innovative techniques to prevent malaria transmission

PASADENA, Calif.-- Bruce A. Hay, associate professor of biology at the California Institute of Technology (Caltech), has been named a 2008 NIH Director's Pioneer Award recipient by National Institutes of Health Director Elias A. Zerhouni, MD.

The Pioneer Awards are a key component of the NIH Roadmap for Medical Research, says Zerhouni. Now in its fifth year, the Pioneer Award program has bestowed 63 awards, 16 of them in 2008. Each Pioneer Award provides $2.5 million in direct costs over five years.

"It's a great honor and privilege to receive a Pioneer Award," Hay says. "It is one of those rare life-changing events in science in which you are given the full resources you need to do the work you have dreamed of doing for years. It's a wonderful opportunity, as well as a challenge."

Zerhouni will announce the 2008 recipients of both the Pioneer Award and the New Innovator Award today at the start of the NIH Director's Pioneer Award Symposium on the NIH's Bethesda, Maryland, campus.

"Nothing is more important to me than stimulating and sustaining deep innovation, especially for early-career investigators and despite challenging budgetary times," Zerhouni says. "These highly creative researchers are tackling important scientific challenges with bold ideas and inventive technologies that promise to break through barriers and radically shift our understanding."

Hay uses genetic and developmental tools to understand and manipulate the biology and genetics of insect populations in the wild. He will be using his Pioneer Award to pursue a strategy for preventing malaria in humans by introducing genes that block transmission of the disease into populations of wild mosquitoes.

"Current approaches to the prevention of mosquito-borne disease such as malaria--which include the use of drugs and insecticides--have proved inadequate," says Hay. "Our goal is to try something different--preventing disease by replacing the wild, disease-transmitting mosquito population with genetically modified counterparts that cannot transmit disease."

Hay has already developed a novel genetic element, dubbed Medea, which he has introduced into the model insect Drosophila. "When Medea is present in a female," Hay explains, "only offspring that carry the element survive. This results in Medea spreading rapidly throughout the population."

Add a gene for disease resistance to the Medea element and it will go along for the ride, spreading just as rapidly.

"The Pioneer Award funds will allow us to adapt this approach to the mosquito," Hay says.

"It is estimated that, somewhere in the world, a child dies of malaria every 30 seconds," says Elliot Meyerowitz, Beadle Professor and chair of the Division of Biology at Caltech. "Bruce's intellectual and experimental work could lead to a solution to this enormous human problem."

Hay received his PhD in neuroscience in 1989 from the University of California, San Francisco. His honors include awards from the Burroughs Wellcome Fund and the Ellison Medical Foundation, as well as a Searle Scholar Award.

Biographical sketches of the new Pioneer Award recipients are at http://nihroadmap.nih.gov/pioneer/Recipients08.aspx. More information on the Pioneer Award can be found at http://nihroadmap.nih.gov/pioneer.

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Lori Oliwenstein
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Scientists Find Our Eyes Evolved for 'X-Ray' Vision

PASADENA, Calif.-- The advantage of using two eyes to see the world around us has long been associated solely with our capacity to see in three dimensions. Now, a new study by scientists at Rensselaer Polytechnic Institute in New York and the California Institute of Technology (Caltech) has uncovered a truly eye-opening advantage to binocular vision: the ability to see through things. 

Most animals--fish, insects, reptiles, birds, rabbits, and horses, for example--live in non-cluttered environments like fields or plains and have eyes located on either side of their head. These sideways-facing eyes give an animal panoramic vision--the ability to see in front and behind itself.

Humans, primates, and other large mammals like tigers, however, have eyes pointing in the same direction. These animals evolved in cluttered environments, such as forests or jungles. Because of their forward-facing eyes, these animals lose the ability to see behind themselves, but they gain a type of X-ray vision that maximizes their ability to see in leafy environments.

So argues Mark Changizi, formerly a postdoctoral scholar at Caltech who is now an assistant professor of cognitive science at Rensselaer, in a new paper that appeared August 28 in the online issue of the Journal of Theoretical Biology. Changizi conducted the research in collaboration with Caltech professor of biology Shinsuke Shimojo.

All animals can see at least parts of the world simultaneously with both eyes. The size of this area, called the binocular region, grows larger as eyes become more forward facing. The binocular region is what makes X-ray vision possible.

Demonstrating this X-ray ability is fairly simple: hold a pen vertically and look at something far beyond it. If you first close one eye, and then the other, you'll see that in each case the pen blocks your view. If you open both eyes, however, you can see through the pen to the world behind it.

"Our binocular region is a kind of 'spotlight' shining through the clutter, allowing us to visually sweep out a cluttered region to recognize the objects beyond it," says Changizi. "As long as the separation between our eyes is wider than the width of the objects causing clutter, we can generally see through it."

To identify which animals have this impressive power, Changizi and Shimojo studied 319 species across 17 mammalian orders. They discovered that eye position depends on two variables: the clutter in an animal's environment, and the animal's body size relative to the objects creating the clutter.

In non-cluttered environments--either non-leafy surroundings, or those where the cluttering objects are larger than the separation between the animal's eyes--animals tend to have sideways-facing eyes.

"Animals outside of leafy environments do not have to deal with clutter no matter how big or small they are, so there is never any X-ray advantage to forward-facing eyes. Because binocular vision does not help them see any better than monocular vision, they are able to survey a much greater region with sideways-facing eyes," Changizi explains.

However, in cluttered environments--leafy surroundings where the cluttering objects are smaller than the separation between an animal's eyes--animals tend to have a wide field of binocular vision, and thus forward-facing eyes.

"This X-ray vision makes it possible for animals with forward-facing eyes to visually survey a much greater region around themselves than sideways-facing eyes would allow," he says.

In such a cluttered environment, the animals' size also matters, Changizi says: "The larger the animal, the more forward facing its eyes will be, to allow for the greatest X-ray vision possible, to aid in hunting, running from predators, and maneuvering through dense forest or jungle."

While human eyes have evolved to be forward facing, Changizi and Shimojo suspect we might actually benefit more from sideways-facing eyes because we live in relatively non-cluttered environments.

"In today's world, humans have more in common visually with tiny mice in a forest than with a large animal in the jungle. We aren't faced with a great deal of small clutter, and the things that do clutter our visual field, like cars and skyscrapers, are much wider than the separation between our eyes, so we can't use our X-ray power to see through them. If we froze ourselves today and woke up a million years from now, it might be difficult for us to look the new human population in the eye, because by then their eyes might be facing sideways."

"This study is nicely consistent with my earlier work with Ken Nakayama in the 1980s, where we provided evidence against the classical notion of binocular vision in that the simultaneous stimulation of two eyes is not critical for binocular integration of visual inputs and stereopsis," says Shimojo.

"Rather," Shimojo adds, "the eye-of-origin information is critical. That is, areas that are viewed by only one eye, and the eye they are viewed by, are very important for an integrated perceptual interpretation of the 3-D environment with the two eyes. This means, also against the classical notion, that the monocular (binocularly unpaired) inputs are, when ecologically valid, not suppressed as noise by interocular suppression. This new piece of work by Mark nicely extends our earlier work into a more comparative, evolutionary, and computational perspective."

The research was funded by the National Institutes of Health.

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Caltech Scientists Discover Why Flies Are So Hard to Swat

PASADENA, Calif.--Over the past two decades, Michael Dickinson has been interviewed by reporters hundreds of times about his research on the biomechanics of insect flight. One question from the press has always dogged him: Why are flies so hard to swat? 

"Now I can finally answer," says Dickinson, the Esther M. and Abe M. Zarem Professor of Bioengineering at the California Institute of Technology (Caltech).

Using high-resolution, high-speed digital imaging of fruit flies (Drosophila melanogaster) faced with a looming swatter, Dickinson and graduate student Gwyneth Card have determined the secret to a fly's evasive maneuvering. Long before the fly leaps, its tiny brain calculates the location of the impending threat, comes up with an escape plan, and places its legs in an optimal position to hop out of the way in the opposite direction. All of this action takes place within about 100 milliseconds after the fly first spots the swatter.

"This illustrates how rapidly the fly's brain can process sensory information into an appropriate motor response," Dickinson says.

For example, the videos showed that if the descending swatter--actually, a 14-centimeter-diameter black disk, dropping at a 50-degree angle toward a fly standing at the center of a small platform--comes from in front of the fly, the fly moves its middle legs forward and leans back, then raises and extends its legs to push off backward. When the threat comes from the back, however, the fly (which has a nearly 360-degree field of view and can see behind itself) moves its middle legs a tiny bit backwards. With a threat from the side, the fly keeps its middle legs stationary, but leans its whole body in the opposite direction before it jumps.

"We also found that when the fly makes planning movements prior to take-off, it takes into account its body position at the time it first sees the threat," Dickinson says. "When it first notices an approaching threat, a fly's body might be in any sort of posture depending on what it was doing at the time, like grooming, feeding, walking, or courting. Our experiments showed that the fly somehow 'knows' whether it needs to make large or small postural changes to reach the correct preflight posture. This means that the fly must integrate visual information from its eyes, which tell it where the threat is approaching from, with mechanosensory information from its legs, which tells it how to move to reach the proper preflight pose."

The results offer new insight into the fly nervous system, and suggest that within the fly brain there is a map in which the position of the looming threat "is transformed into an appropriate pattern of leg and body motion prior to take off," Dickinson says. "This is a rather sophisticated sensory-to-motor transformation and the search is on to find the place in the brain where this happens," he says.

Dickinson's research also suggests an optimal method for actually swatting a fly. "It is best not to swat at the fly's starting position, but rather to aim a bit forward of that to anticipate where the fly is going to jump when it first sees your swatter," he says.

The paper, "Visually Mediated Motor Planning in the Escape Response of Drosophila," will be published August 28 in the journal Current Biology.

The research was funded by the National Institutes of Health and the National Science Foundation.

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Caltech Neurobiologists Discover Individuals Who "Hear" Movement

PASADENA, Calif.-- Individuals with synesthesia perceive the world in a different way from the rest of us. Because their senses are cross-activated, some synesthetes perceive numbers or letters as having colors or days of the week as possessing personalities, even as they function normally in the world. Now, researchers at the California Institute of Technology have discovered a type of synesthesia in which individuals hear sounds, such as tapping, beeping, or whirring, when they see things move or flash. Surprisingly, the scientists say, auditory synesthesia may not be unusual--and may simply represent an enhanced form of how the brain normally processes visual information.

Psychologists previously reported visual, tactile, and taste synesthesias, but auditory synesthesia had never been identified. Caltech lecturer in computation and neural systems Melissa Saenz discovered the phenomenon quite by accident.

"While I was running an experiment at the Caltech Brain Imaging Center, a group of students happened to pass by on a tour, and I volunteered to explain what I was doing," explains Saenz, who, along with Christof Koch, the Lois and Victor Troendle Professor of Cognitive and Behavioral Biology at Caltech and professor of computation and neural systems, reports the finding in the August 5 issue of the journal Current Biology.

"As part of the experiment, a moving display was running on my computer screen with dots rapidly expanding out, somewhat like the opening scene of Star Wars. Out of the blue, one of the students asked, "Does anyone else hear something when you look at that?" After talking to him further, I realized that his experience had all the characteristics of a synesthesia: an automatic sensory cross-activation that he had experienced all of his life," says Saenz.

A search of the synesthesia literature revealed that auditory synesthesia--of any kind--had never been reported. Intrigued, Saenz began to look for other individuals with the same ability, using the original movie seen by the student as a test. "I queried a few hundred people and three more individuals turned up," she says. "Having that specific example made it easy to find more people. That movie just happens to be quite "noisy" to the synesthetes and was a great screening tool. When asked if it made a sound, one of the individuals responded, "how could it not?" I would have been less successful had I just generally asked, "Do you hear sounds when you see things move or flash?" because in the real environment, things that move often really do make a sound," for example, a buzzing bee.

This may be why auditory synesthesia hadn't been detected by neurobiologists. "People with auditory synesthesia may be even less likely than people with other synesthetic associations to fully realize that their experience is unusual. These individuals have an enhanced soundtrack in life, rather than a dramatically different experience, compared to others," says Saenz. However, when asked, all of the synesthetes could name examples of daily visual events that caused sounds that they logically knew to be only in their minds, such as seeing a fluttering butterfly or watching television with the sound turned off.

Saenz and Koch found that the four synesthetes outperformed a group of nonsynesthetes on a simple test involving rhythmic patterns of flashes similar to visual Morse code. Normally, such patterns are easier to identify with sound (beeps) than with vision (flashes), so the researchers predicted that synesthetes would have an advantage with visual patterns because they actually heard a sound every time they saw a flash.

In the test, the subjects saw a series of flashes and had to guess if a second sequence, played afterward, represented the same temporal pattern or not. As a baseline measurement, a similar test was given using sequences of beeps. Both the synesthetes and the control group performed equally well when given beeps. However, with visual flashes synesthetes were much more accurate, responding correctly more than 75 percent of the time, compared to around 50 percent--the level predicted by chance--in the control group. "Synesthetes had an advantage because they not only saw but also heard the visual patterns," Saenz says.

Saenz and Koch suspect that as much as 1 percent of the population may experience auditory synesthesia. In fact, she and Koch think that the brain may normally transfer visual sensory information over to the auditory cortex, to create a prediction of the associated sound. "This translation might result in actual sound perception in synesthetes, perhaps due to stronger than normal connections, says Saenz, who has begun brain imaging experiments to study this connectivity in synesthetes and nonsynesthetes.

"We might find that motion processing centers of the visual cortex are more interconnected with auditory brain regions than previously thought, even in the 'normal' brain," Saenz says. "At this point, very little is known about how the auditory and visual processing systems of the brain work together. Understanding this interaction is important because in normal experience, our senses work together all the time."

The work was supported by the Mind Science Foundation, the Gordon and Betty Moore Foundation, the Mathers Foundation, and the National Institute of Mental Health.

View the video used to identify auditory synesthetes, in a quiet location, at http://www.klab.caltech.edu/~saenz/movingdots.html.

 

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Caltech Researchers Discover Dual-Use Sexual Attraction and Population-Control Chemicals in Nematodes

Pasadena, Calif.--Organisms ranging from humans to plants to the lowliest bacterium use molecules to communicate. Some chemicals trigger the various stages of an organism's development, and still others are used to attract members of the opposite sex. Researchers at the California Institute of Technology have now found a rare kind of signaling molecule in the nematode worm Caenorhabditis elegans that serves a dual purpose, working as both a population-control mechanism and a sexual attractant.

The discovery, published online July 23 in the journal Nature, could lead to new ways to control parasitic nematodes, which affect the health of more than a billion people and each year cause billions of dollars in crop damage.

Caenorhabditis elegans worms have long been a favorite model organism among developmental biologists, in part because of their small size (1 mm long), simple nervous system, and ease of care. The normally soil-dwelling worms are almost always hermaphrodites--females that are capable of making sperm, with which they can fertilize their own eggs. About one in every 1000 worms is a true male.

Researchers studying C. elegans had long noted that hermaphroditic worms, left to wander about in a culture plate, will secrete a chemical that strongly attracts males. When males are exposed to the chemical, dubbed "worm sweat" by C. elegans researchers, "males will act as if their desired mate is near, and start blindly feeling around to locate it," says molecular geneticist Paul W. Sternberg, the Thomas Hunt Morgan Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute.

Jagan Srinivasan, a postdoctoral research scholar at Caltech, Sternberg, and his colleagues at the University of Florida, the United States Department of Agriculture, and Cornell University, assayed and analyzed worm sweat and found that it consisted of a blend of three related chemicals, called ascarosides. The chemicals looked suspiciously like another compound previously known to be involved in triggering an alternative developmental state in the nematodes, a spore-like condition called the "dauer stage"--from the German word for "enduring"--that represents a form of worm population control.

"When worm larvae are stressed out and hungry and crowded," Sternberg says, "they enter the dauer stage." In this alternate state, the worm larvae can withstand harsh environmental conditions. "The dauer stage is important because it is the infective stage in a lot of parasitic nematodes," he says.

The scientists found that purified samples of the chemicals, dubbed ascr#2, ascr#3, and ascr#4, induced sexual excitement among males, but only when the chemicals were combined, and only when presented to the worms in very dilute form. At higher concentrations, 100 to 1000 times stronger, males were repelled, sexual reproduction ceased, and existing worm larvae entered their hibernating stage.

"This is the first glimpse into the chemical code that nematodes are using to communicate," says Sternberg. Adds Srinivasan, "It is the first time that two distinct and different life history traits--reproduction and developmental arrest--have been found to be regulated by the same family of molecules, suggesting a link, which we had not suspected, between the corresponding pathways."

The discovery offers hope for a solution to a global nematode scourge. Hundreds of thousands of nematode species occupy the earth, and many are pests or parasites whose activities cause disease or economic hardship, with damage amounting to billions of dollars per year. For example, hookworm, a parasitic nematode that lives in the small intestine of humans, is believed to infect one billion people worldwide and in developing countries is the leading cause of illnesses in babies, children, pregnant women, and malnourished individuals; the soybean cyst nematode, which attacks the roots of soybean plants, causes half a billion dollars worth of crop loss each year in the United States alone.

By decoding some of the signals that nematodes use to communicate, scientists may be able to offer new strategies to control the pests. One option could be to create chemical attractants derived from pheromones, similar to the pheromone-based substances that now are used to lure fruit flies and other bugs into traps. Alternatively, Sternberg says, compounds could be developed "that interfere with the chemical signaling involved in the reproductive process," thereby preventing the organism from multiplying.

The paper, "A blend of small molecules regulates both mating and development in Caenorhabditis elegans," was published July 23 in the early online edition of Nature and will appear in the August 28 print edition. The work was supported by the Human Frontiers Science Program, the National Institutes of Health, and the Howard Hughes Medical Institute.

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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.

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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.

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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.

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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. 

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