National Human Genome Research Institute awards $12 million, five-year grant to "WormBase"

PASADENA, Calif.— The Caltech-led WormBase project, an ongoing multi-institutional effort to make genetic information on the experimental animal known as C. elegans freely available to the world, has been augmented with a new $12 million grant from the National Human Genome Research Institute. The money will be distributed over five years for ongoing work on the genome database, which since its inception in 2000 has become a major resource for biomedical researchers as well as biologists attempting to better understand individual genes and how they interrelate. According to Caltech biology professor Paul Sternberg, leader of the project, WormBase has already succeeded in making available on-line the complete genome sequence (100.2 million base pairs) of the nematode, plus an almost complete sequence for the closely related organism C. briggsae, as well as genes for some 20 parasitic nematode species. In addition, the project makes available a huge amount of experimental data pertaining to the nematode.

The completed sequences will be vital for an emerging research effort that includes the new double-strand RNA interference technique for understanding a gene's function, and the fruits of the sequencing effort are already apparent. There are now 23,000 such experiments in WormBase, along with 280,000 DNA expression ("chip") microarray observations, as well as detailed information on the expression of more than 1,600 of the worm's 20,000 genes.

"For the future, researchers will look at interactions between genes, which means that there are 20,000-squared possibilities for the interactions of two genes alone," says Sternberg. "Also, our future effort will include working with similar databases of the genomes of other organisms, such as the mouse, fruit fly, and yeast, for shared software and shared conceptual vocabularies.

"The ultimate purpose is to allow medical researchers to get the information more easily," he adds.

The human-worm connection may seem tenuous to people outside biology, but it is known that the two organisms have similarity in about 40 percent of their genes. A very realistic motivation for the funding of genome sequencing of other organisms has been to provide data for comparisons of genes that are of interest in the quest to better understand human disease. Thus, a cancer researcher who discovers that a certain gene is expressed in cancer cells can use the WormBase to see if the gene exists in nematodes, and if so, what is known about the gene's function.

Exploring the fundamental relationships between genes from species separated by hundreds of millions of years of evolution is expected to be a cornerstone of 21st-century biological innovation. Improved knowledge of how a gene is expressed in one species--and as time goes on, how two or more genes interact--will provide new approaches for dealing with human disease and will almost certainly be the foundation for some important medical advances.

The role of WormBase in 21st-century medicine will continue to be as a resource for knowledge. Already the wormbase.org site is fully searchable in a number of ways, including by genes, cells (the nematodes have only 959, and all are clearly understood and clearly visible under a microscope), and biological processes, as well as by names of researchers.

Information in WormBase comes from teams at the two centers that sequence the C. elegans and C. briggsae genomes--a team at the Sanger Institute, in England, led by Richard Durbin, and one at Washington University, led by John Spieth. The innovative software used to display the information in WormBase was developed by Lincoln Stein of the Cold Spring Harbor Laboratory, where the WormBase Web server is located.

Fourteen individuals at Caltech are currently involved in the WormBase project, including nine biologists and three computer experts.

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Why Fearful Animals Flee—or Freeze

PASADENA, Calif. –In most old-fashioned black-and-white horror flicks, it always seems there's some hapless hero or heroine who gets caught up in a life-threatening situation. Instead of making the obvious choice--to run like hell--he/she freezes in place. That decision, alas, leads to their ultimate demise.

While their fate was determined by bad scriptwriting, scientists already know that in real life, environment and experience influence defensive behaviors. Less understood are the neural circuits that determine such decisions. Now, in an article in the May 1 issue of the Journal of Neuroscience, researchers at the California Institute of Technology have developed an experimental model using mice that can map and manipulate the neural circuits involved in such innate behaviors as fear.

Raymond Mongeau, Gabriel A. Miller, Elizabeth Chiang, and David J. Anderson, in work performed at Caltech, manipulated either a flight or freeze reaction in mice through the use of an ultrasonic auditory stimulus, and further, were able to alter the mouse's behavior by making simple changes in the animal's environment. They also found that flight and freezing are negatively correlated, suggesting that a kind of competition exists between these alternative defensive motor responses. Finally, they have begun to map the potential circuitry in the brain that controls this competition.

"Fear and anxiety are important emotions, especially in this day and age," says Anderson, a Caltech professor of biology and an investigator with the Howard Hughes Medical Institute. "We know a lot about how the brain processes fear that is learned, but much less is known about innate or unlearned fear. Our results open the way to better understanding how the brain processes innately fearful stimuli, and how and where anxiety affects the brain to influence behavior."

Using the ultrasonic cue, the researchers were able to predict and manipulate the animal's reaction to a fearful situation. They found that mice exposed to the ultrasonic stimulus in their home cage (a familiar environment) predominantly displayed a flight response. Those placed in a new cage (an unfamiliar environment), or treated with foot shocks the previous day, primarily displayed freezing and less flight.

Anderson noted that in previous fear "conditioning" experiments, where mice learn to fear a neutral tone associated with a footshock, the animals show only freezing behavior and never flight, even though in the wild, flight is a normal and important fear response to predators. This suggests that the ultrasonic stimulus used by Anderson and colleagues is tapping into brain circuits that mediate natural, or innate, fear responses that include flight as well as freezing.

What causes the shift from flight to freezing behavior? Probably high anxiety and stress, say the authors, caused by an unfamiliar environment or the foot shocks. The researchers suggest that freezing requires a higher threshold level of anticipatory fear (the heroine inside a dark, spooky house) before it can be elicited by the ultrasound.

Most brain researchers believe the brain uses a hierarchy of neural systems to determine which defensive behaviors, like flight or freezing, to use. These range from an evolutionary older neural system that generates "quick and dirty" defensive strategies, to more evolved systems that produce slower but more sophisticated reactions. These systems are known to interact, but the neural mechanisms that decide which response wins out are not understood.

One of the goals of their work was to map the brain regions that control the behaviors triggered by the fear stimulus, to observe whether any change in brain activity correlated with the different defensive behaviors. They achieved this, all the way down to the resolution of a single neuron, by mapping the expression pattern of the c-FOS gene, a so-called "immediate early gene" that is turned on when neurons are excited. The switching on of the c-FOS gene can therefore be used as an indication of neuronal activation.

A map of the c-FOS expression patterns during flight vs. freezing revealed that mice displaying freezing behavior had neural activity in different regions of the brain than those that fled. Some of these regions were previously known to inhibit each other, providing a possible explanation for the apparent competition between flight and freezing observed in the intact animal.

Anderson notes that more work needs to be done to pin down where and how anxiety modifies defensive behavior. "This system may also provide a useful model for understanding the neural substrates of human fear disorders, like panic and anxiety," says Anderson, "as well as provide a model for developing drugs to treat them."

Contact: Mark Wheeler (626) 395-8733 wheel@caltech.edu

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Caltech biology professor to directresearch program on brain signaling

California Institute of Technology biologist Mary Kennedy has been named project director for a $4 million federal project grant to better understand how the brain processes signals. Progress could lead to new insights into how drugs can be better custom-designed to treat a host of neurodegenerative disorders, mental illnesses, and disabilities, including Alzheimer's disease, depression, and schizophrenia.

The funding will come from the National Institute of Neurological Disorders and Stroke, a component of the National Institutes of Health (NIH). According to Kennedy, who is the Allen and Lenabelle Davis Professor of Biology at Caltech, the five-year project is innovative because it will integrate advanced computational methods with experiments to better analyze and model calcium signaling in the brain. In addition to Kennedy's research group at Caltech, the program will involve research teams from the Salk Institute, Cold Spring Harbor Laboratory, and the University of North Carolina.

"Another aspect of this research that is quite new is the application of these kinds of methods at the molecular level," she says. "This is important because, for about 20 years or so, it wasn't really possible to be rigorously quantitative about the biochemical functions of synapses at the molecular level. This was because we didn't know all the molecules that were involved."

With new advances, especially the completion of the Human Genome Project, it is now time for a new phase in research on the molecular mechanisms of brain functions, according to Kennedy. In addition to basic improvements in knowledge of how brain signaling works, the research program could also lead indirectly to pharmaceutical advances.

"Neurological and mental diseases result, in part, from derangements in regulation of synaptic transmission," Kennedy says. "In a type of neuronal structure known as dendritic spines -- so named because they sort of look like spines -- calcium influx through a certain type of receptor is a principal regulator of synaptic strength, or plasticity. Thus, calcium can lead to increases or decreases, of varying durations, in synaptic strength."

The program includes four projects and a core that will provide new computer software. One project will use a computer program called MCell to develop and test models of calcium dynamics in spines. Another will rely on microscopy to study the organization of calcium sources and sinks in spines, as well as calcium distribution. A third, which will be centered in Kennedy's lab, will develop and test kinetic models of enzymes regulated by calcium; and a fourth will use advanced imaging techniques to measure calcium signals and their regulation in individual spines.

The program will be highly interdisciplinary, Kennedy says. Three physicists will be among the team members in her lab. Work at the other institutions, as well, will involve specialists from disciplines outside biology.

"Once we have a better quantitative understanding of signaling, it will be possible to ask much 'cleaner' questions about what kind of drugs will treat certain conditions, and under what circumstances."

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New Insight Into How Flies Fly

PASADENA, Calif. –How does a fly fly and why should we care? To the first, says Michael Dickinson, a professor of bioengineering at the California Institute of Technology, the short answer is different from what we have thought, and he and his colleagues used a dynamically-scaled flapping robot (aka Robofly), a free flight arena (aka Fly-O-Rama), and a 3D, infrared visual flight simulator (Fly-O-Vision) to prove it.

And we should care, says Dickinson, because the simple motion of a flying fly links a series of fundamental and complex processes within both the physical and biological sciences. Studying a fly may eventually lead to a model that will provide insight into the behavior and robustness of complex systems in general, and, for roboticists, may help them in the design of flying robots that mimic nature.

In a paper entitled "The Aerodynamics of Free Flight Maneuvers in Drosophila," Steven Fry of the University of Zurich, Rosalyn Sayaman, a Caltech research assistant, and Dickinson show how tiny insects use their wings to generate enough torque to overcome inertia, and not--as conventional wisdom has held--friction. The paper will appear in the April 18 issue of the journal Science.

Flies and other dipterans (insects within the family that includes houseflies, hoverflies, and fruit flies), are capable of making rapid 90-degree turns, called saccades, at "extraordinary" speeds, says Dickinson, less than 50-thousandths of a second. That's faster, he says, "than a human eye can blink." To make the turn, a fly must generate enough torque, or twisting force, to offset two forces working against it--the inertia of its own body and the viscous friction of air.

Until now, it's always been assumed that viscosity, a resistance to flow, is the enemy for small critters, while inertia is the bane of larger animals like birds. But the theory has never been tested.

To study the aerodynamics of active flight maneuvers, the researchers employed infrared, three-dimensional, high-speed video (the Fly-O-Vision) to capture the fruit fly, Drosophila melanogaster, performing saccades in free flight. The animals were released in a large, enclosed arena (the Fly-O-Rama), and lured toward a vertical cylinder laced with a drop of vinegar. As the flies approach the cylinder, it looms within their field of view, triggering a rapid turn that helps the fly avoid a collision.

Many flies performed saccades within the intersecting fields of view of the three cameras, which allowed the researchers to film the turn, measure the wing and body position throughout the maneuver, and calculate the velocity of its path.

The improved resolution of the 3D video showed that, despite its small size and slow speed (relative to other animals), the fly performed a banked turn, similar to those observed in larger fly species, first accelerating, then slowing as it changed heading, then accelerating again at the end of the turn. This suggests that the time and velocity of the small fly are dominated by body inertia and not friction.

To see if the measured patterns of wing motion were sufficient to explain the saccades, the researchers played the sequences through a dynamically scaled robotic model (you guessed it, Robofly) to measure the aerodynamic forces as they vary by time. They found that the time and torque they calculated based on the fly's body morphology and body motion from the video matched "amazingly well," says Dickinson, with the calculations derived from the wing motion of the robot. These results, he notes, further support the notion that even in small insects the torques created by the wings act primarily to overcome inertia and not friction.

Although these experiments were performed on tiny fruit flies, says Dickinson, the results impact nearly all insects, because the importance of inertia over friction increases with the size of the animal. The results also provide a basis for future research on the neural and mechanical basis of insect flight, and, for roboticists, may offer insights for the design of biomimetic flying devices. It may also yield a little respect for the common fly. As Rosalyn Sayaman puts it on her web page, "I now love flies. I used to just shoo and swat. Now, I can't even swat anymore."

Note to Editors: Video and still photos are available.

Contact: Mark Wheeler (626) 395-8733 wheel@caltech.edu

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Six Caltech Professors Awarded Sloan Research Fellowships

PASADENA, Calif.— Six Caltech professors recently received Alfred P. Sloan Research Fellowships for 2003.

The Caltech recipients in the field of chemistry are Paul David Asimow, assistant professor of geology and geochemistry, Linda C. Hsieh-Wilson, Jonas C. Peters, and Brian M. Stoltz, assistant professors of chemistry. In mathematics, a Sloan Fellowship was awarded to Danny Calegari, associate professor of mathematics, and in neuroscience, to Athanassios G. Siapas, assistant professor of computation and neural systems.

Each Sloan Fellow receives a grant of $40,000 for a two-year period. The grants of unrestricted funds are awarded to young researchers in the fields of physics, chemistry, computer science, mathematics, neuroscience, computational and evolutionary molecular biology, and economics. The grants are given to pursue diverse fields of inquiry and research, and to allow young scientists the freedom to establish their own independent research projects at a pivotal stage in their careers. The Sloan Fellows are selected on the basis of "their exceptional promise to contribute to the advancement of knowledge."

From over 500 nominees, a total of 117 young scientists and economists from 50 different colleges and universities in the United States and Canada, including Caltech's six, were selected to receive a Sloan Research Fellowship.

Twenty-eight former Sloan Fellows have received Nobel prizes.

"It is a terrific honor to receive this award and to be a part of such a tremendous tradition of excellence within the Sloan Foundation," said Stoltz. Asimow commented that he will use his Sloan Fellowship to "support further investigation into the presence of trace concentrations of water in the deep earth... I'm pleased because funds that are unattached to any particular grant are enormously useful for seeding new and high-risk projects that are not quite ready to turn into proposals." On his research, Peters said, "The Sloan award will provide invaluable seed money for work we've initiated in the past few months regarding nitrogen reduction using molecular iron systems."

The Alfred P. Sloan Research Fellowship program was established in 1955 by Alfred P. Sloan, Jr., who was the chief executive officer of General Motors for 23 years. Its objective is to encourage research by young scholars at a time in their careers when other support may be difficult to obtain. It is the oldest program of the Alfred P. Sloan Foundation and one of the oldest fellowship programs in the country.

Contact: Deborah Williams-Hedges (626) 395-3227 debwms@caltech.edu

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Caltech Professor Receives Award for Research into Mechanisms of Memory Formation

PASADENA, Calif.— How do we form short-term and long-term memories in the brain? A California Institute of Technology professor will try to answer this question and others. Athanassios Siapas, assistant professor of computation and neural systems, has been awarded a $445,120 grant by the James S. McDonnell Foundation for his project "Network Mechanisms of Memory Formation."

The establishment of long-term memories is a gradual process that involves intricate interactions across distributed networks of neurons in the brain. Until recently, the direct experimental observation of such interactions was not technically feasible. Using techniques that enable monitoring of the simultaneous activity of large numbers of single neurons across multiple brain areas, Siapas's research group will study the mechanisms that orchestrate memory formation in distributed brain circuits.

Understanding the fundamental principles that underlie memory formation and learning may offer insights into neurological disorders that affect memory, such as Alzheimer's disease, and may aid in finding a cure for such debilitating illnesses.

Siapas joined Caltech in January 2002, after conducting postdoctoral work at the Center for Learning and Memory at the Massachusetts Institute of Technology. Siapas also earned his PhD from MIT.

Founded in 1950 by aerospace pioneer James S. McDonnell, the James S. McDonnell Foundation was established to improve the quality of life, and has done so by contributing to the generation of new knowledge through its support of research and scholarship. In 2002 the foundation awarded approximately $16 million in grants. Since its inception, the McDonnell Foundation has awarded over $264 million in grants.

Contact: Deborah Williams-Hedges (626) 395-3227 debwms@caltech.edu

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Caltech, Italian Scientists Find Human Longevity Marker

"A very short one." Oldest known living person in 1995, Jeanne Calment, of France, then 120, when asked what sort of future she anticipated having. Quoted in Newsweek magazine, March 6, 1995.

PASADENA, Calif. – Even though Jeanne Louise Calment died in 1997 at the age of 122, we envy her longevity. Better, perhaps, to envy her mother's lineage, suggest scientists at the California Institute of Technology.

In a study of nonrelated people who have lived for a century or more, the researchers found that the centenarians had something in common: each was five times more likely than the general population to have the same mutation in their mitochondrial DNA (mtDNA).

That mutation, the researchers suggest, may provide a survival advantage by speeding mtDNA replication, thereby increasing its amount or replacing that portion of mtDNA which has been battered by the ravages of aging

The study was conducted by Jin Zhang, Jordi Asin Cayuela, and Yuichi Michikawa, postdoctoral scholars; Jennifer Fish, a research scientist; and Giuseppe Attardi, the Grace C. Steele Professor of Molecular Biology, all at Caltech, along with colleagues from the Universities of Bologna and Calabria in Italy, and the Italian National Research Center on Aging. It appears in the February 4 issue of the Proceedings of the National Academy of Sciences, and online at the PNAS website (http://www.pnas.org/).

Mitochondrial DNA is the portion of the cell DNA that is located in mitochondria, the organelles which are the "powerhouses" of the cell. These organelles capture the energy released from the oxidation of metabolites and convert it into ATP, the energy currency of the cell. Mitochondrial DNA passes only from mother to offspring. Every human cell contains hundreds, or, more often, thousands of mtDNA molecules.

It's known that mtDNA has a high mutation rate. Such mutations can be harmful, beneficial, or neutral. In 1999, Attardi and other colleagues found what Attardi described as a "clear trend" in mtDNA mutations in individuals over the age of 65. In fact, in the skin cells the researchers examined, they found that up to 50 percent of the mtDNA molecules had been mutated.

Then, in another study two years ago, Attardi and colleagues found four centenarians who shared a genetic change in the so-called main control region of mtDNA. Because this region controls DNA replication, that observation raised the possibility that some mutations may extend life.

Now, by analyzing mtDNA isolated from a group of Italian centenarians, the researchers have found a common mutation in the same main control region. Looking at mtDNA in white blood cells of a group of 52 Italians between the ages of 99 and 106, they found that 17 percent had a specific mutation called the C150T transition. That frequency compares to only 3.4 percent of 117 people under the age of 99 who shared the same C150T mutation.

To probe whether the mutation is inherited, the team studied skin cells collected from the same individuals between 9 and 19 years apart. In some, both samples showed that the mutation already existed, while in others, it either appeared or became more abundant during the intervening years. These results suggest that some people inherit the mutation from their mother, while others acquire it during their lifetime.

Confirmation that the C150T mutation can be inherited was obtained by looking at mtDNA samples from 20 monozygotic (that is, derived from a single egg) twins and 18 dizygotic (from separate eggs) twins between 60 and 75 years of age. To their surprise, the investigators found that 30 percent of the monozygotic twins and 22 percent of the dizygotic twins shared the C150T mutation.

"The selection of the C150T mutation in centenarians suggests that it may promote survival," says Attardi. "Similarly, it may protect twins early in life from the effects of fetal growth restriction and the increased mortality associated with twin births.

"We found the mutation shifts the site at which mtDNA starts to replicate, and perhaps that may accelerate its replication, possibly, allowing the lucky individual to replace damaged molecules faster." Attardi says the study is the first to show a robust difference in an identified genetic marker between centenarians and younger folks. Their next goal, he says, is to find the exact physiological effect of this particular mutation.

The researchers who contributed to the paper in Italy were Massimiliano Bonafe, Fabiola Olivieri, Giuseppe Passarino, Giovanna De Benedictis, and Claudio Franceschi.

Contact: Mark Wheeler (626) 395-8733 wheel@caltech.edu

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Research shows that shear force of blood flowis crucial to embryonic heart development

In a triumph of bioengineering, an interdisciplinary team of California Institute of Technology researchers has imaged the blood flow inside the heart of a growing embryonic zebrafish. The results demonstrate for the first time that the very action of high-velocity blood flowing over cardiac tissue is an important factor in the proper development of the heart—a result that could have profound implications for future surgical techniques and even for genetic engineering.

In the January 9, 2003 issue of the journal Nature, the investigators report on two interrelated advances in their work on Danio rerio, an animal reaching only two inches in length as an adult but a model of choice for research in genetic and developmental biology. First, the team was able to get very-high-resolution motion video, through the use of confocal microscopy, of the tiny beating hearts that are less than the diameter of a human hair. Second, by surgically blocking the flow of blood through the hearts, the researchers were able to demonstrate that a reduction in "shear stress," or the friction imposed by a flowing fluid on adjacent cells, will cause the growing heart to develop abnormally.

The result is especially important, says co-lead author Jay Hove, because it shows that more detailed studies of the effect of shear force might be exploited in the treatment of human heart disease. Because diseases such as congestive heart failure are known to cause the heart to enlarge due to constricted blood flow, a better understanding of the precise mechanisms of the blood flow could perhaps lead to advanced treatments to counteract the enlargement.

Also, Hove says, a better understanding of genetic factors involving blood flow in the heart—a future goal of the team's research—could eventually be exploited in the diagnosis of prenatal heart disease for early surgical correction, or even genetic intervention.

Hove, a bioengineer, along with Liepmann Professor of Aeronautics and Bioengineering Morteza Gharib, teamed with Scott Fraser, who is Rosen Professor of Biology, and Reinhardt Köster, a postdoctoral scholar in Fraser's lab, to study the heart development of zebrafish. Gharib, a specialist on fluid flow, has worked on heart circulation in the past, and Fraser is a leading authority on the imaging of cellular development in embryos. The new results are thus an interdisciplinary marriage of the fields of engineering, biology, and optics.

"Our research shows that the shape of the heart can be changed during the embryonic stage," says Hove. "The results invite us to consider whether this can be related to the roots of heart failure and heart disease."

The researchers keyed their efforts on the zebrafish because the one-millimeter eggs and the embryos inside them are nearly transparent. With the addition of a special chemical to further block the formation of pigment, the team was able to perform a noninvasive, in vivo "optical dissection." To do this, they used a technique known as confocal microscopy, which allows imaging of a layer of tissue. The images are two-dimensional, but they can be "stacked" for a three-dimensional reconstruction.

Concentrating on two groups of embryos—one group 36 hours after fertilization and the other at about four days—the researchers discovered that their deliberate interference with the blood flow through the use of carefully placed beads had a profound effect on heart development. When the shear force was reduced by 90 percent, the tiny hearts did not form valves properly, nor did they "loop," or form an outflow track properly.

Because the early development of an embryonic heart is thought to proceed through several nearly identical stages for all vertebrates, the researchers say the effect should also hold true for human embryos. In effect, the research demonstrates that the shear force should also be a fundamental influence on the formation of the various structures of the human heart.

The next step for the researchers is to attempt to regulate the restriction of shear force through new techniques to see how slight variations affect structural development, and to look at how gene expression is involved in embryonic heart development. " What we learn will give us directions to go and questions to ask about other vertebrates, particularly human beings," Hove says.

In addition to the lead authors Hove and Köster and professors Gharib and Fraser, the team also included Caltech students Arian S. Forouhar and Gabriel Acevedo-Bolton.

The paper is available on the Nature Web site at http://www.nature.com/nature/links/030109/030109-1.html

Contact: Robert Tindol (626) 395-3631

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Caltech, UCLA Researchers Create a New Gene Therapy for Treatment of HIV

PASADENA, Calif.— California Institute of Technology and UCLA researchers have developed a new gene therapy that is highly effective in preventing the HIV virus from infecting individual cells in the immune system. The technique, while not curative, could be used as a significant new treatment for people already infected by reducing the HIV-infected cells in their bodies.

Also, the new approach could be used to fight other diseases resulting from gene malfunctions, including cancer.

Reporting in the current issue of the Proceeding s of the National Academy of Sciences (PNAS), Caltech biologist David Baltimore and his UCLA collaborators announce that the new technique works by using a disabled version of the AIDS virus as a sort of "Trojan horse" to get a disruptive agent inside the human T-cells, thereby reducing the likelihood that a potent HIV virus will be able to successfully invade the cell. Early laboratory results show that more than 80 percent of the T-cells may be protected.

"To penetrate a cell, HIV needs two receptors that operate like doorknobs and allow the virus inside," says Baltimore, who is president of Caltech. "HIV grabs the receptor and forces itself into the cell. If we can knock out one of these receptors, we hope to prevent HIV from infecting the cell."

The receptors in question are called the CCR5 and the CD4. The human immune system can't get along without the CD4, but about 1 percent of the Caucasian population is born without the CCR5. In fact, these people are known to have a natural immunity to AIDS.

Therefore, the researchers' strategy was to disrupt the CCR5 receptor. They did this by introducing a special double-stranded RNA known as "small interfering RNA," or siRNA, into the T-cell. To do so, they engineered a disabled HIV virus to carry the siRNA into the T-cell. Thus, the T-cell was invaded, but the disabled virus has no ability to cause disease. Once inside the T-cell, the siRNA knocks out the CCR5 receptor.

Laboratory results show that human T-cells thus protected are then quite resistant to infection by the HIV virus. When the T-cells were put in a petri dish and exposed to HIV, less than 20 percent of the cells were actually infected.

"Synthetic siRNAs are powerful tools," says Irvin S.Y. Chen, one of the authors of the paper and director of the UCLA AIDS Institute. "But scientists have been baffled at how to insert them into the immune system in stable form. You can't just sprinkle them on the cells."

The other two authors of the paper are Xiao-Feng Qin, a postdoctoral researcher at Caltech; and Dong Sung An, a postdoctoral researcher at UCLA. The two contributed equally to the work.

The technique should become a significant new means of treating people already infected with HIV, Baltimore and Chen say.

"Our findings raise the hope that we can use this approach or combine it with drugs to treat HIV in people—particularly in persons who have not experienced good results with other forms of treatment," says Baltimore.

The technique can also potentially be used for other diseases when a specific gene needs to be knocked out, such as the malfunctioning genes associated with cancer, Chen says. "We can easily make siRNAs and use the carrier to deliver them into different cell types to turn off a gene malfunction," he says.

In addition, the technique could be used to prevent certain microorganisms from invading the body, Baltimore adds.

The research is supported by the National Institute of Allergy and Infectious Diseases and the Damon Runyon-Walter Winchell Fellowship.

[Note to editors: UCLA is also issuing a news release on this research. Contact Elaine Schmidt at (310) 794-2272; elaines@support.ucla.edu]

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Caltech Professor Receives McKnight Award for Brain Disease Research

PASADENA, Calif. — The McKnight Endowment Fund for Neuroscience will award $300,000 over three years to California Institute of Technology biology professor Paul H. Patterson for research he is conducting on mental illness.

Patterson is one of seven researchers nationally who are each being awarded the same amount in order to further their studies into diagnosing, preventing, and treating injuries or diseases affecting the brain and spinal cord.

Patterson's research is "A Mouse Viral Model for Study of the Pathogenesis and Prevention of Mental Illness." It is based on the knowledge that when a pregnant mother contracts influenza at a certain stage of pregnancy, there is an increase in the chance that her child will be schizophrenic, or possibly autistic. Patterson uses a mouse model to determine how maternal infection causes defects in fetal brain development, and to attempt to prevent the brain abnormalities.

Other McKnight Neuroscience of Brain Disorders Awards will go to U.S. scientists investigating Alzheimer's disease, epilepsy, mood disorders, schizophrenia, and spongiform encephalopathies.

The McKnight Endowment Fund created the Neuroscience of Brain Disorders Awards to help translate basic laboratory discoveries in neuroscience into clinical benefits for patients. The first such awards were given in 2001.

"Neuroscience has made tremendous progress over the last few decades, and that progress is reflected in the research proposals we see," said Larry R. Squire, chair of the awards committee. Dr. Squire is a professor of psychiatry, neurosciences, and psychology at the University of California at San Diego School of Medicine, and research career scientist at the Veterans Affairs Medical Center, San Diego. "Scientists not only are exploring fundamental questions about the structure and function of the nervous system but are finding applications for their work in the clinical arena," he said.

The McKnight Endowment Fund for Neuroscience is an independent organization funded solely by the McKnight Foundation of Minneapolis, Minnesota, and led by a board of prominent neuroscientists from around the country. The McKnight Foundation has supported neuroscience research since 1977. The foundation established the Endowment Fund in 1986 to carry out one of the intentions of founder William L. McKnight (1887-1979). One of the early leaders of the 3M Company, he had a personal interest in memory and its diseases and wanted part of his legacy used to help find cures.

The Endowment Fund makes three types of awards each year. In addition to the McKnight Neuroscience of Brain Disorders Awards, they are the McKnight Technological Innovations in Neuroscience Awards, providing seed money to develop technical inventions to advance brain research; and the McKnight Scholar Awards, supporting neuroscientists in the early stages of their research careers.

Caltech Contact: Jill Perry, Media Relations Director (626) 395-3226 jperry@caltech.edu

McKnight Foundation Contact: Kathleen Rysted krysted@mcknight.org

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