Caltech Scientists Show Function of Helical Band in Heart

MRI technique provides evidence that could both settle a 50-plus-year debate and create a roadmap for future cardiac surgical techniques

PASADENA, Calif.--Scientists from the California Institute of Technology (Caltech) have created images of the heart's muscular layer that show, for the first time, the connection between the configuration of those muscles and the way the human heart contracts.

More precisely, they showed that the muscular band--which wraps around the inner chambers of the heart in a helix--is actually a sort of twisting highway along which each contraction of the heart travels.

Their findings were published in the December issue of the American Physiological Society journal, Heart and Circulatory Physiology.

Since the days of Leonardo da Vinci, observers of the human body have known that the heart's beat is not a simple in-and-out movement--that it has more than a little bit of a twist to it. "The heart twists to push blood out the same way you twist a wet towel to wring water out of it," explains Morteza Gharib, the principal investigator on the study, and the Hans W. Liepmann Professor of Aeronautics and professor of bioengineering in the Division of Engineering and Applied Science at Caltech.

Some 50 years ago, anatomist Francisco Torrent-Guasp was the first to show the helical configuration of the heart's myocardium--its muscular middle layer, the one that contracts with each heart beat.

But what he and subsequent generations of scientists were unable to do was to connect that myocardial band to the heart's function--to prove that the helical shape is important to the effective beating of the heart. Without that connection, physicians and scientists have tended to look at the heart as "just a piece of meat," says Gharib.

Until now, that is. Using a technique pioneered by Han Wen and his team at the National Institutes of Health, Gharib and his colleague Abbas Nasiraei Moghaddam, a Caltech graduate and visitor in bioengineering, were able to create some of the first dynamic images of normal myocardium in action at the tissue level. "We tagged and traced small tissue elements in the heart, and looked at them in space, so we could see how they moved when the heart contracts," Gharib explains. "In this way, we were able to see where the maximum physical contraction occurs in the heart and when--and to show that it follows this intriguing helical loop."

With each beat of the heart, a wave of contraction starts at the heart's apex--which, despite its name, is actually at the very bottom of the heart--and then travels up through the myocardium. "The only time the whole helix shows up in the images is at the end of systole, which is when the heart is contracting," says Gharib. "This simple band structure is akin to an engine behind the heart pumping action."

In addition to going a long way toward settling the decades-long structure/function debate surrounding Torrent-Guasp's work, this finding also has major implications for the surgical treatment of heart disease, Gharib says. "It's going to change the way we repair the heart," he explains. Knowing that the contractile wave travels along the helical pathway--instead of occurring throughout the heart all at once--has implications for which parts of the heart will be most vulnerable to a surgeon's scalpel, for instance. "Seventy-five percent of the function of the heart depends on this muscle," Gharib says. "Surgeons now know what to cut and what not to cut. This will help them to come up with new and more effective surgical procedures."

The work detailed in the paper, "Evidence for the existence of a functional helical myocardial band," was supported by funding from the Caltech MRI Center through a Discovery grant.

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Caltech Scientists Develop "Barcode Chip" for Cheap, Fast Blood Tests

PASADENA, Calif.-- A new "barcode chip" developed by researchers at the California Institute of Technology (Caltech) promises to revolutionize diagnostic medical testing. In less than 10 minutes, and using just a pinprick's worth of blood, the chip can measure the concentrations of dozens of proteins, including those that herald the presence of diseases like cancer and heart disease.

The device, known as the Integrated Blood-Barcode Chip, or IBBC, was developed by a group of Caltech researchers led by James R. Heath, the Elizabeth W. Gilloon Professor and professor of chemistry, along with postdoctoral scholar Rong Fan and graduate student Ophir Vermesh, and by Leroy Hood, president of the Institute for Systems Biology in Seattle, Washington.

An IBBC, described in a paper in the advance online edition of Nature Biotechnology, is about the size of a microscope slide and is made out of a glass substrate covered with silicone rubber. The chip's surface is molded to contain a microfluidics circuit--a system of microscopic channels through which the pinprick of blood is introduced, protein-rich blood plasma is separated from whole blood, and a panel of protein biomarkers is measured from the plasma.

The chip offers a significant improvement over the cost and speed of standard laboratory tests to analyze proteins in the blood. In traditional tests, one or more vials of blood are removed from a patient's arm and taken to a laboratory, where the blood is centrifuged to separate whole blood cells from the plasma. The plasma is then assayed for specific proteins. "The process is labor intensive, and even if the person doing the testing hurries, the tests will still take a few hours to complete," says Heath. A kit to test for a single diagnostic protein costs about $50.

"We wanted to dramatically lower the cost of such measurements, by orders of magnitude," he says. "We measure many proteins for the cost of one. Furthermore, if you reduce the time it takes for the test, the test is cheaper, since time is money. With our barcode chip, we can go from pinprick to results in less than 10 minutes."

A single chip can simultaneously test the blood from eight patients, and each test measures many proteins at once. The researchers reported on devices that could measure a dozen proteins from a fingerprick of blood, and their current assays are designed for significantly more proteins. "We are aiming to measure 100 proteins per fingerprick within a year or so. It's a pretty enabling technology," Heath says.

To perform the assay, a drop of blood is added to the IBBC's inlet, and then a slight pressure is applied, which forces the blood through a channel. As the blood flows, plasma is skimmed into narrow channels that branch off from the main channel. This part of the chip is designed as if it were a network of resistors, which optimizes plasma separation.

The plasma then flows across the "barcodes." The barcodes consist of a series of lines, each 20 micrometers across and patterned with a different antibody that allows it to capture a specific protein from the plasma passing over. When the barcode is "developed," the individual bars emit a red fluorescent glow, whose brightness depends upon the amount of protein captured.

In the Nature Biotechnology paper, the researchers used the chip to measure variations in the concentration of human chorionic gonadotropin (hCG), the hormone produced during pregnancy. "The concentration of this protein increases by about 100,000-fold as a woman goes through the pregnancy cycle, and we wanted to show that we could capture that whole concentration range through a single test," Heath says.

The scientists also used the barcode chip to analyze the blood of breast and prostate cancer patients for a number of proteins that serve as biomarkers for disease. The types and concentrations of the proteins vary from disease to disease and between different individuals. A woman with breast cancer, for example, will produce a different suite of biomarkers than will a man with prostate cancer, while a woman with an aggressive form of cancer may produce proteins that are different from a woman with a less-deadly cancer.

Those proteins can also change as a patient receives therapy. Thus, determining these biomarker profiles can allow doctors to create individualized treatment plans for their patients and improve outcomes. The ease and the speed with which results can be obtained using the IBBC also will potentially allow doctors to assess their patients' responses to drugs and to monitor how those responses evolve with time, much as a diabetic patient might use a blood glucose test to monitor insulin delivery.

The barcode chip is now being tested in human clinical trials on patients with glioblastoma, a common and aggressive form of brain tumor. The researchers are also using the chips in studies of healthy individuals, to determine how diet and exercise change the composition of the proteins in the blood.

Currently, the barcoded information is "read" with a common laboratory scanner that is also used for gene and protein expression studies. "But it should be very easy to design something like a supermarket UPC scanner to read the information," making the process even more user-friendly, says Fan, the first author on the paper.

"As personalized medicine develops, measurements of large panels of protein biomarkers are going to become important, but they are also going to have to be done very cheaply," Heath says. "It is our hope that these IBBCs will enable such inexpensive and multiplexed measurements."

The paper, "Integrated barcode chips for rapid, multiplexed analysis of proteins in microliter quantities of blood," will be featured as the cover story in the December print edition of Nature Biotechnology. The work was funded by the National Cancer Institute and by the Institute for Collaborative Biotechnologies through a grant from the United States Army Research Office.

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Caltech's David Baltimore and Fiona Harrison Named among America's Best Leaders for 2008

U.S. News Media Group and Harvard's Center for Public Leadership recognize 24 of the country's foremost professionals

PASADENA, Calif.--Two prominent researchers from the California Institute of Technology (Caltech) have been named among the country's 24 top leaders by U.S. News Media Group in association with the Center for Public Leadership (CPL) at Harvard Kennedy School. The 2008 edition of America's Best Leaders--available online at www.usnews.com/leaders and on newsstands Monday, November 24--includes honors for Caltech's David Baltimore and Fiona Harrison.

According to U.S. News, the Best Leaders issue features "some of the country's most visionary individuals," highlighting those professionals "who continue to offer optimism and hope through their work."

Nobel Laureate David Baltimore, the Robert Andrews Millikan Professor of Biology and former president of Caltech, was lauded by the magazine for the way he has "profoundly influenced national science policy on such issues as recombinant DNA research and the AIDS epidemic. He is an accomplished researcher, educator, administrator and public advocate for science and engineering, and is considered one of the world's most influential biologists."

Baltimore was awarded the Nobel Prize in Physiology or Medicine in 1975, at the age of 37. He served as president of Caltech for nine years and was named president emeritus in 2006. He had previously spent almost 30 years on the faculty of the Massachusetts Institute of Technology, where he contributed widely to the understanding of cancer, AIDS, and the molecular basis of the immune response, and where he served as founding director of the Whitehead Institute for Biomedical Research from 1982 until 1990. He served as president of the American Association for the Advancement of Science from 2007 to 2008, and is currently its chair.

Baltimore says he is "very honored to be named among this exceptional group of leaders."

Leadership, he says, "involves a vision of the future, and a generosity of spirit that allows the leader to take pleasure in the accomplishments of others." Leadership can't be about micromanaging every aspect of a large organization, he notes. "It's about picking the right people, motivating them, and encouraging them. You have to make sure those people are pulling in the same direction. You have to catalyze interaction between people so that they see a commonality of interests--so that they follow a common line."

Fiona Harrison, a professor of physics and astronomy at Caltech, was chosen for her work as principal investigator of the NuSTAR (Nuclear Spectroscopic Telescope Array) Mission, a pathfinder mission that will "open the high energy X-ray sky for sensitive study for the first time," she says. She started developing the technologies necessary to realize NuSTAR more than a decade ago, and assembled and led a team of scientists and engineers to design and implement the mission. NuSTAR was selected by NASA through a competitive process and will launch in mid-2011.

Harrison "has devoted her career to studying energetic phenomena in the Universe, including massive black holes and stellar explosions, and developing advanced instrumentation for focusing and detection of X-rays and gamma-rays," notes U.S. News. She is a recipient of a NASA Graduate Student Research Fellowship and winner of the Robert A. Millikan Prize Fellowship in Experimental Physics, and was awarded a Presidential Early Career Award for Scientists and Engineers by President Clinton. She joined the faculty of Caltech in 1995.

"It is an honor to be recognized among such a diverse and distinguished group of people," says Harrison.

"Most aspiring scientists don't focus on leadership as a quality necessary to accomplish their research," she adds. "As experiments and projects get larger and more complex, however, good leadership is often necessary in order to make progress. For me, creating and motivating an effective team were skills I learned in order to make the science I am passionate about happen."

In a collaborative effort between U.S. News and Harvard's CPL, the leaders were selected by a nonpartisan and independent committee, convened and organized by the center, without the participation of U.S. News editors. The selection criteria used by the committee in choosing the honorees included the ability to set direction, achieve results, and cultivate a culture of growth.

"Even though Americans have lost confidence in current leadership, over the past year they have had unique opportunities to observe and debate the qualities of strong leaders," says Brian Kelly, editor of U.S. News & World Report. "With our Best Leaders issue, we widen the lens to examine people who are showing leadership in unexpected ways across a wide variety of fields."

Other honorees include Lance Armstrong, founder of the Lance Armstrong Foundation; Herbie Hancock, chairman of the Thelonious Monk Institute of Jazz Performance Arts; Marian Wright Edelman, founder and president of the Children's Defense Fund; Anthony Fauci, director of the National Institute for Allergy and Infectious Disease; Robert Gates, U.S. Secretary of Defense; and Steven Spielberg, director and producer, and founder of the Shoah Foundation.

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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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