Caltech Researchers Use Electron Cryotomography to Get First 3-D Glimpse of Bacterial Cell-Wall Architecture

Findings represent important advances in both biology and imaging technology

PASADENA, Calif.--The bacterial cell wall that is the target of potent antibiotics such as penicillin is actually made up of a thin single layer of carbohydrate chains, linked together by peptides, which wrap around the bacterium like a belt around a person, according to research conducted by scientists at the California Institute of Technology (Caltech). This first-ever glimpse of the cell-wall structure in three dimensions was made possible by new high-tech microscopy techniques that enabled the scientists to visualize these biological structures at nanometer scales.

"This is both a technological and biological advance," says Grant Jensen, associate professor of biology at Caltech, a Howard Hughes Medical Institute investigator, and the principal investigator on the study.

Their research appears in the online early edition of the Proceedings of the National Academy of Sciences (PNAS).

"Bacterial cells rely on a cage-like net that surrounds them to maintain their integrity," Jensen explains. "If it weren't for this molecular bag, the bacteria couldn't survive; they would likely rupture."

This bag, called a sacculus, is made out of peptidoglycan, a mesh-like structure of carbohydrates (glycans) and amino-acid peptides. It is the sacculus, Jensen notes, that is targeted by the antibiotic penicillin; penicillin blocks a bacterium's ability to grow and remodel the bag to fit it as the bacterium itself grows. "If the bug can't make this bag," Jensen says, "it can't multiply, and you get better."

Researchers have long been interested in understanding the precise architecture of the sacculus. In particular, Jensen and his colleagues have wondered whether the so-called glycan strands--which are cross-linked by peptides to create peptidoglycan--"wrap around the cell like a belt wraps around a person," or whether they stand up from the surface of the bacterial cell, "like grass."

The answer to this debate has eluded the scientists, however, because trying to image such tiny biological objects has been beyond their technological reach. Until now, that is.

"Six years ago, a gift from the Moore Foundation allowed us to buy what is arguably the world's best electron cryomicroscope," says Jensen. "This allowed us to take a different kind of picture of small biological objects than has ever been possible before. These pictures are 3-D images to molecular resolution--you can actually start to see individual biological molecules. Using it, we were able to see this network of glycan strands. It was just remarkable."

By pairing the electron cryotomography and a purification technique that involved removing the sacculi and flattening them in a very thin layer of water, postdoctoral scholar Lu Gan, the paper's first author and a Damon Runyon Fellow, was able to image the peptidoglycan structure in three dimensions, which allows for a virtual 3-D tour of the bacterial sacculus.

"What we saw were long skinny tubes wrapping around the bag like the ribs of a person or a belt around the waist," says Jensen. "We also saw that the sacculus is just a single layer thick."

"This is a clear answer to this old question," adds Gan. "We now know what the architecture of this most basic shape-determining molecule is. We now know the right answer versus having a family of answers, some of which are wrong."

Understanding how the cell wall is built is important, says Jensen, because scientists have long been in the dark about some of the most basic physical and mechanical aspects of bacterial life, including why they are shaped the way they are. "It's hard to understand how a building is constructed unless you can see the studs," he explains. "Now that we can see the studs--now that we can see the basic architecture of the sacculus--we're closer to understanding how a bacterium could direct its own growth, and how drugs that block that process might work."

Also involved in the research reported in PNAS was Songye Chen, a postdoctoral scholar in biology at Caltech.

The paper, "Molecular organization of gram-negative peptidoglycan," was published in the PNAS Early Edition. This work was supported by grants from the National Institutes of Health, a Searle Scholar Award, Caltech's Beckman Institute, and gifts from the Gordon and Betty Moore Foundation and the Agouron Institute. Lu Gan is supported by a fellowship from the Damon Runyon Cancer Research Foundation.

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Caltech Biologists Spy on the Secret Inner Life of a Cell

PASADENA, Calif.-- The transportation of antibodies from a mother to her newborn child is vital for the development of that child's nascent immune system. Those antibodies, donated by transfer across the placenta before birth or via breast milk after birth, help shape a baby's response to foreign pathogens and may influence the later occurrence of autoimmune diseases. Images from biologists at the California Institute of Technology (Caltech) have revealed for the first time the complicated process by which these antibodies are shuttled from mother's milk, through her baby's gut, and into the bloodstream, and offer new insight into the mammalian immune system.

Newborns pick up the antibodies with the aid of a protein called the neonatal Fc receptor (FcRn), located in the plasma membrane of intestinal cells. FcRn snatches a maternal antibody molecule as it passes through a newborn's gut; the receptor and antibody are enclosed within a sac, called a vesicle, which pinches off from the membrane. The vesicle is then transported to the other side of the cell, and its contents--the helpful antibody--are deposited into the baby's bloodstream.

Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute, and her colleagues were able to watch this process in action using gold-labeled antibodies (which made FcRn visible when it picked up an antibody) and a technique called electron tomography. Electron tomography is an offshoot of electron microscopy, a now-common laboratory technique in which a beam of electrons is used to create images of microscopic objects. In electron tomography, multiple images are snapped while a sample is tilted at various angles relative to the electron beam. Those images can then be combined to produce a three-dimensional picture, just as cross-sectional X-ray images are collated in a computerized tomography (CT) scan.

"You can get an idea of movement in a series of static images by taking them at different time points," says Bjorkman, whose laboratory studies how the immune system recognizes its targets, work that is offering insight into the processes by which viruses like HIV and human cytomegalovirus invade cells and cause disease.

The electron tomography images revealed that the FcRn/antibody complexes were collected within cells inside large vesicles, called "multivesicular bodies," that contain other small vesicles. The vesicles previously were believed to be responsible only for the disposal of cellular refuse and were not thought to be involved in the transport of vital proteins.

The images offered more surprises. Many vesicles, including multivesicular bodies and other more tubular vesicles, looped around each other into an unexpected "tangled mess," often forming long tubes that then broke off into the small vesicles that carry antibodies through the cell. When those vesicles arrived at the blood-vessel side of the cell, they fused with the cell membrane and delivered the antibody cargo. The vesicles also appeared to include a coat made from a molecule called clathrin, which helps form the outer shell of the vesicles. Researchers previously believed that a vesicle's clathrin cage was completely shed before the vesicle fused with the cell membrane. The new results suggest that only a small section of that coating is sloughed off, which may allow the vesicle to more quickly drop its load and move on for another.

"We are now studying the same receptor in different types of cells in order to see if our findings can be generalized, and are complementing these studies with fluorescent imaging in live cells," Bjorkman says. "The process of receptor-mediated transport is fundamental to many biological processes, including detection of developmental decisions made in response to the binding of hormones and other proteins, uptake of drugs, signaling in the immune and nervous systems, and more. So understanding how molecules are taken up by and transported within cells is critical for many areas of basic and applied biomedical research," she adds.

The paper, "FcRn-mediated antibody transport across epithelial cells revealed by electron tomography," was published in the September 25 issue of Nature. The work was supported by the National Institutes of Health, a Max Planck Research Award, the Gordon and Betty Moore Foundation, the Agouron Institute, and National University of Singapore AcRF start-up funds.

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Caltech Scientists Engineer Supersensitive Receptor, Gain Better Understanding of Brain's Dopamine System

Receptor may be good target for treatment of smoking addiction, ADHD, and more

PASADENA, Calif.--Genetically modifying a receptor found on the neurons that produce the neurotransmitter dopamine has given California Institute of Technology (Caltech) researchers a unique glimpse into the workings of the brain's dopamine system--as well as a new target for treating diseases that result from either too much or too little of this critical neurotransmitter.

Caltech scientists Henry Lester, Bren Professor of Biology, and Ryan Drenan, senior postdoctoral scholar in biology, worked with colleagues from Caltech, the University of Colorado at Boulder, the Rockefeller University, the University of Utah, and the pharmaceutical company Targacept. They genetically modified a type of brain receptor known as an "a6-containing nicotinic acetylcholine receptor" to make it more sensitive to both nicotine and acetylcholine. (Acetylcholine is another of the brain's neurotransmitters.)

The receptor in question is found primarily on neurons that produce the neurotransmitter dopamine. When the receptor is kicked into action by the presence of either nicotine or acetylcholine--two of the keys that fit its biochemical lock--the receptor prompts the neurons on which it sits to begin pumping out dopamine.

While previous studies of this same receptor had shown what happens when you block its function--when you put the brakes on dopamine production--this was the first time anyone was able to look at what happens when you make the receptor more sensitive and thus put the dopamine system into overdrive. "We were able to not only isolate this receptor's function, but also to amplify it," says Drenan, "and that allowed us to see exactly what it and it alone is capable of doing in the brain."

As it turns out, it's capable of doing a lot. Revved up by even low doses of nicotine, these receptors prompt the neurons on which they are clustered to let loose with a flood of dopamine. This flooding was obvious from the behavior of mice carrying the genetically modified receptors: because dopamine plays an important role in movement, the mice became quickly and significantly hyperactive. In fact, the researchers note, low doses of nicotine affect mice with these hypersensitive receptors in much the same way that amphetamines affect "normal" mice. Looking more closely at this phenomenon, the researchers write, "could be useful in understanding the causes of human hyperactivity such as that observed in ADHD." "This technique also gives researchers the power to activate dopamine neurons selectively," says Lester. "We plan to exploit this opportunity to obtain new knowledge about dopamine neurons' functions."

While these sensitized receptors appear on dopamine neurons throughout the brain, the researchers note that they seem to play an especially critical role in what is called the mesolimbic pathway--one of four pathways that control dopamine production throughout the brain, and the one implicated in the addictive properties of drugs like nicotine.

To this end, Lester's team and their collaborators have already begun to explore the possibilities of targeting these receptors with specific drugs that might work to reduce their sensitivity to nicotine, potentially providing a new line of attack for treating nicotine addiction. In fact, notes Drenan, these same drugs might also one day prove useful in treating other dopamine-related conditions, such as ADHD, Parkinson's disease, and schizophrenia.

"By uncovering the biological role of these receptors, especially with regard to their role in the midbrain dopamine system, we show that they are excellent drug targets," says Drenan.

The paper, "In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity a6* Nicotinic Acetylcholine Receptors," was published in the October 9 issue of the journal Neuron. This work was supported by grants from the National Institutes of Health, the Moore Foundation, the Croll Research Foundation, California's Tobacco-Related Disease Research Program, a Caltech alumnus, and the Howard Hughes Medical Institute.

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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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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.

Writer: 
Kathy Svitil
Writer: 

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.

Writer: 
Elisabeth Nadin
Writer: 

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