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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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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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.

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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. 

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Elisabeth Nadin
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