Engineering Populations of Wild Insects to Fight Disease

PASADENA, Calif.-- Malaria infects more than half a billion people every year, and kills more than one million, mostly children. Despite decades of effort, no effective vaccine exists for the disease, caused by single-celled Plasmodium parasites. The parasites are transmitted to humans via the bite of infected mosquitoes.

One way to stop malaria is to make the mosquitoes that carry the disease themselves resistant to the pathogen. Getting disease-fighting genes into the mosquito population can be tricky, however, because bugs carrying disease-resistance genes are likely to be less reproductively fit than their wild counterparts, and thus less likely to spread their genes naturally.

Associate Professor of Biology Bruce Hay of the California Institute of Technology, postdoctoral fellow Chun-Hong Chen, and their colleagues at Caltech and the University of California, Los Angeles, have come up with a novel method for introducing such genes into insect populations. The work, published recently in the journal Science, involves the creation of a selfish genetic element that is uniquely adapted to spread itself quickly throughout the population.

"This spread is essential," says Hay, "because people who live in areas affected by malaria and other mosquito-borne diseases are bitten often, so there will be little benefit unless most of the mosquito population is disease resistant."

"What we need," says Chen, the first author of the study, "is some way of forcing, or helping, these disease-resistance genes to spread rapidly throughout the wild population."

The technique Chen, Hay, and their colleagues have come up with uses a maternal-effect dominant embryonic arrest--or Medea--genetic element, a particularly spiteful selfish genetic element.

"Selfish genetic elements (single genes or clusters of genes) are basically units of genetic information that are more successful than your average gene at passing themselves from generation to generation," says Chen, even if their presence makes an organism less fit. "Our idea was to create a selfish genetic element that could be linked with a specific cargo, the disease-resistance gene, as a way of rapidly carrying this gene through the population."

Medea elements were first described in 1992 by Richard Beeman and colleagues at Kansas State University, who found the entity in populations of the common flour beetle Tribolium castaneum.

Beeman and his colleagues do not yet know the molecular nature of Tribolium Medea, but their work suggests that Medea consists of two linked genes. One gene, whose expression is activated in the mother, encodes a toxin that is deposited into all oocytes, or eggs. Embryos that do not inherit a Medea element die because of the toxin. Embryos that inherit Medea from either their mother's or their father's genome, however, will survive because they produce an antidote that neutralizes the toxin. As a result, chromosomes that carry Medea end up in offspring more often than those that do not, and Medea can spread rapidly through a population.

"We spent several years trying to create a selfish genetic element based on these principles," says Chen, "but it was difficult to get the insects to produce just the right amount of toxin; enough to kill the embryo, but not so much that the toxin couldn't be inhibited by the antidote." The researchers eventually switched to a system in which the toxin caused the loss of an essential function, and the antidote restored that function. "We generated flies in which maternal expression of small noncoding RNAs, known as microRNAs, were used to silence a gene known as myd88, which is crucial for embryonic development. Embryos from mothers expressing these microRNAs all died, unless they also expressed a microRNA-insensitive version of the myd88 gene: the antidote," said Chen.

Fruit flies carrying this synthetic Medea element spread quickly throughout a laboratory population of wild-type flies. After just a few generations, all of the flies in the population carried at least one copy of Medea. "To our knowledge this work represents the first de novo synthesis of a selfish genetic element able to drive itself into a population. It provides a simple proof-of-principle experiment demonstrating that, at least in a highly controlled laboratory environment, in a model organism, we can change the genetic makeup of a population," says Hay.

The team now plans to use the technique to transmit a real payload--a disease-resistance gene--into the mosquito.

Says Hay: "Mosquitoes with a decreased capacity to transmit malaria and other mosquito-borne diseases have already been identified in the wild and created in the laboratory by other researchers. These observations tell us that we can manipulate the mosquito immune system and thereby, at least in principal, stop this and other mosquito-borne diseases at their source in the mosquito. When combined with a mechanism such as Medea that helps to spread these resistance genes through the wild population, there is a real possibility that disease transmission can be suppressed in an environmentally friendly way that does not involve the wholesale use of insecticides or modification of the environment; the mosquitoes will still be there but with one or two tiny genetic changes that make them unable to transmit these dreadful diseases."

"This work is a prime example of how fundamental research can lead to breakthroughs that have huge implications for bettering human health," says Marion Zatz, chief of the Developmental and Cellular Processes Branch at the National Institute of General Medical Sciences, which partially supported the research. "Dr. Hay's work on how microRNAs regulate cell death in the innocuous fruit fly has 'borne fruit' in potential applications for limiting the spread of malaria."

This work was supported by National Institutes of Health grants GM057422 and GM70956 to Bruce Hay, and NS042580 and NS048396 to Ming Guo, assistant professor in the departments of neurology and pharmacology at UCLA's Brain Research Institute, David Geffen School of Medicine.

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Contact: Kathy Svitil (626) 395-8022 ksvitil@caltech.edu

Visit the Caltech Media Relations Web site at: http://pr.caltech.edu/media.

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Researchers Stimulate Growth of Neural Stem Cells in Adult Brain for Treatment of Neurological Disorders

PASADENA, Calif.—In a development that could potentially benefit victims of degenerative neurological diseases, researchers have succeeded in stimulating the growth of adult neural stem cells. Such cells could then be directed towards repairing one's own brain.

In the November 15 issue of the Journal of Neuroscience, California Institute of Technology neuroscientists report that they have discovered a way to stimulate an area of the brain where adult stem cells normally exist. As a result, there is a significant increase in stem cell production—up to six times the normal amount of adult neural stem cells found there.

According to Paul Patterson, the Biaggini Professor of Biological Sciences at Caltech and senior author of the paper, the good news is that these stem cells represent a large pool of precursor cells that future work may direct into pathways for replacement of dying cells in disorders such as Parkinson's and Alzhiemer's diseases and multiple sclerosis.

"Basically, what my colleague Sylvian Bauer has done is take a natural protein in the body called leukemia inhibitory factor, or LIF, and inject it into the brains of adult mice," Patterson explains. "The results show that you can stimulate the subventricular zone to produce a much larger pool of adult neural stem cells."

The idea then is to direct the stem cells to form the necessary specialized neurons or glia in the part of the brain that is damaged by disease or injury, Patterson says.

"Neuroscientists have known for some time that the adult brain possesses neural stem cells that could be used to regenerate neurons, and in fact, the brains of neurodegenerative disease patients show evidence that their neural stem cells do attempt to replace dying cells.

"However, the contribution of these cells to brain repair is currently very limited," he says. "Our approach may overcome the limitation of cell numbers, and the approach of using one's own cells offers the further advantage of avoiding the transplantation of immunologically foreign stem cells, thereby eliminating the problems of rejection."

This development in no way renders the use of embryonic stem cells obsolete, or argues against further research with embryonic stem cells, Patterson says. Embryonic stem cells have the potential to become any cell in the body, whereas his process uses adult neural stem cells for brain disorders only.

Although this stimulation of neural stem cell growth has been done in laboratory mice, Patterson says that humans also have neural stem cells in the adult brain.

The next step is to see if the adult neural stem cells can be directed to replace cells in mice with brains that are damaged in ways similar to humans with Parkinson's, Alzheimer's, and multiple sclerosis.

Bauer, the lead author of the paper, is a former postdoctoral researcher in Patterson's lab who recently moved to the Université Paul Cézanne, Aix-Marseille III, in France.

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California Purple Sea-Urchin Genome Sequenced by International Team

PASADENA, Calif.—A group of 240 researchers from more than 70 institutions has announced the sequencing of the male California purple sea urchin. An animal frequently used in experiments, its genome has been studied intensely for years at Caltech's Kerckhoff Marine Biological Laboratory (KML), and will contribute significantly to biomedical advances of the future.

Reporting in the November 10 issue of the journal Science, the researchers are announcing that the high-quality "draft" sequence covers more than 90 percent of the sea-urchin genome. In addition to the primary results in Science, 41 companion manuscripts will appear in Science and a special issue of the December 1 issue of Developmental Biology.

The project was led by Erica Sodergren and George Weinstock, a husband-and-wife team at the Baylor College of Medicine-Human Genome Sequencing Center (BCM-HGSC), along with Richard Gibbs, director of the BCM-HGSC, and Eric Davidson and Andrew Cameron of the California Institute of Technology. The National Human Genome Research Institute of the National Institutes of Health provided most of the funding for the sequencing and annotation.

According to the researchers, the sea-urchin genome contains more than 814 million letters, spelling out 23,300 genes. To date, nearly 10,000 of the genes have been scrutinized by the international consortium.

The results are the outcome of work begun at Caltech more than 30 years ago, when Davidson and Roy Britten, a scientist working at Caltech's Kerckhoff Marine Biological Laboratory, began to exploit the utility of the sea urchin as an experimental animal and decided to develop it as a model system in the then emerging field of molecular biology. In the ensuing years many advances in cell and developmental biology derived from this decision.

"Roy Britten and Eric Davidson offered a comprehensive theory of gene regulation in higher organisms, and the sea urchin has been the premier model for testing these predictions," says Gibbs. "The complete sequence is now available to further these studies."

More recently, Davidson and Cameron have coordinated efforts to have the sea-urchin genome sequenced. Starting with a special grant from the Stowers Institute for Medical Research in Kansas City, they assembled the research materials that would be needed to sequence the genome at the Sea Urchin Genome Facility in Caltech's Beckman Institute and at the KML.

A culture system at KML in which the purple sea urchin is grown through the life cycle continues to provide the essential infrastructure. When the Human Genome Research Institute announced a way to propose additional genome sequencing to support the human genome information, the team at the BCM-HGSC was poised to take action. From these roots grew the Sea Urchin Genome Sequencing Consortium.

Sea urchins are echinoderms (Greek for spiny skin), marine animals that originated over 540 million years ago and that include starfish, brittle stars, sea lilies, and sea cucumbers. Following the great extinction of animals 250 million years ago, the modern sea urchins emerged as the dominant echinoderm species. The purple sea urchin emerged in the North Pacific Ocean during a rapid burst of speciation and diversification 15-20 million years ago.

There was great interest in the sea urchin as a target for genome sequencing because these animals share a common ancestor with humans. That ancestor lived over 540 million years ago and gave rise to the Deuterostomes, the superphylum of animals that includes phyla such as echinoderms and chordates, the phylum to which humans and other vertebrates belong. All Deuterostomes are more closely related to each other than they are to any other animals not included in the Deuterostome superphylum. For example, among sequenced genomes, the genomes of fruit flies and worms are more distant from the sea urchin genome than is the human genome. "Each genome that we sequence brings new surprises. This analysis shows that sea urchins share substantially more genes and biological pathways with humans than previously suspected," says Francis S. Collins, director of the National Human Genome Research Institute. "Comparing the genome of the sea urchin with that of the human and other model organisms will provide scientists with novel insights into the structure and function of our own genome, deepening our understanding of the human body in health and disease." To discover how sea urchins and humans can be so different, yet be related by descent from an ancient relative, their genomes were compared. The sea urchin is an invertebrate and the first example of sequencing a Deuterostome genome outside the chordates. Most previous invertebrate genomes that were sequenced, such as insects and nematodes, were animals outside the Deuterostome superphylum, although one genome of a chordate invertebrate, the sea squirt, has been sequenced. The sea urchin lies evolutionarily in a large niche between the chordate branch of the Deuterostomes and the non-Deuterostome superphyla. "The sea urchin fills a large evolutionary gap in sequenced genomes," says Weinstock, co-director of Baylor's Human Genome Sequencing Center. "It allows us to see what went on in evolution after the split between the ancestors that gave rise to humans and insects. The sea urchin genome provided plenty of unexpected rewards and was a great choice for sequencing." The comparison of the genes of the sea urchin to the human gene list shows which human genes are likely to be recent innovations in human evolution and which are ancient. It also shows which human genes have changed slowly in the lineage from the ancestral Deuterostome animal and which genes are evolving rapidly in response to natural selection. This will make it possible one day to know the history of every human gene-and build a picture of what the extinct ancestors that gave rise to animal life ranging from worms to humans looked like. Although invertebrate sea urchins have a radically different morphology from humans and other vertebrates, their embryonic development displays basic similarities, an important shared property of Deuterostome animals. This distinguishes them from Protostomes, which have a different pattern of embryonic development. This makes the sea urchin, with its many useful properties such as transparent embryos and ease of isolation of eggs and sperm, a valuable model for studying the process of development and helping us to understand human development. The development of the animal occurs through a complex network of genes, making the sea urchin one of the main models for systems biology, which describes how the building blocks of an animal interact in time and space. Sea urchins provide a rapid and efficient gene transfer system. By injecting DNA into the egg, researchers can determine which letters spell instructions for turning genes on and off. The series of genetic switches leading to the ordered cascade of expression of genes after fertilization in the sea urchin is among the best understood developmental systems among animal models. Now, with the genome sequence in hand, a more complete set of components of development are known, and this process can be studied exhaustively.

Because of its evolutionary position, the sea-urchin genome sequence was a sample of unknown biological territory. Some of the notable surprises and discoveries were that: —The sea urchin has most of the same gene families found in human beings. These gene families make up the Deuterostome tool kit used to create animals in this superphylum. However, the size of gene families is often larger in humans, reflecting, in part, two whole genome duplication events during vertebrate evolution after the separation of the sea urchin and human evolutionary lines. —One unexpected exception to this size rule is the immune system. Humans have innate and acquired immune systems. The sea urchin has some of the genes of the acquired immune system, but its innate immune branch is greatly expanded with ten- to twenty times as many genes as in humans. —Innate immunity is the set of proteins that are "hard wired" to detect unique molecules within bacteria, such as their cell walls, and to signal that there is an intruder. This rich repertoire of sea urchin proteins could turn out to provide new reagents in the fight against infectious diseases. —The sea urchin has genes for sensory proteins that are involved in human vision and hearing. Yet the sea urchin has no eyes and ears, at least as we know them. Some of the visual sensory proteins are localized within an appendage known as the tube foot, and likely function in sensory processes there. It is remarkable that the same sensory proteins are used in organs with such different structures in sea urchins and humans. "The sea urchin reminds us of the underlying unity of all life on earth," notes Sodergren. "It is a similar set of genes and proteins being reused in different ways, different numbers, and at different times in the life cycle to create the diversity of living forms." The sea-urchin genome was one of the most challenging to sequence to date at Baylor. The genome is highly polymorphic, meaning that the two copies of the genome in the diploid organism vary from each other by about 4 percent, or one difference in spelling every 25 letters. This posed a formidable challenge in assembling the nine million separate short sequences produced by DNA sequencing. A new approach was used, emphasizing the use of BAC clones as a framework. Each BAC clone represents only one version of the genome spelling, and thus provides a consistent sequence on which to build the genome. To sequence the 8,000 BAC clones covering the genome, another new technique was used. The process, CAPSS (clone-array pooled shotgun sequencing), sequences mixtures of BAC clones, rather than individual ones, and then assigns portions of the mixture of sequences to the proper clone. This reduces the cost and time to do the genome by an order of magnitude. The sea-urchin project was thus a test bed for innovations in whole genome sequencing. The sea-urchin project is one of more than 20 projects involving animal genomes that Baylor's Human Genome Sequencing Center has undertaken, including the human genome and those of primates like the rhesus monkey, other mammals like the cow and wallaby, insects such as the honey bee, beetle, and wasp, and most recently the dolphin. In addition, numerous microbes have been sequenced, with a focus on infectious diseases. Other projects include studying the genetic basis of human disease, and this will be the major emphasis of future work.

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Caltech, UC Berkeley to Investigate How Brain Activity Controls Complex Behavior

PASADENA, Calif.—A new $4.4-million grant from the National Science Foundation will allow researchers at the California Institute of Technology and the University of California, Berkeley, to develop techniques to turn brain cells on and off in animals as they go about their daily activities, allowing the scientists to understand the details of how brain activity leads to complex behaviors.

According to principal investigator Michael Dickinson, the Zarem Professor of Bioengineering at Caltech, the five-year program is aimed at solving one of the remaining great challenges facing biologists—understanding the mechanistic basis of complex behavior. The work will focus on fruit flies, which are a powerful model system understood extremely well at the genetic level.

"New approaches available in molecular genetics can now be applied to manipulate individual brain cells in an attempt to understand how brains control behavior," says Dickinson. "We'll also use recent advances in engineering to create new devices to observe and measure behavioral changes in a manner as rigorous as those available to detect genetic differences."

The work will involve experiments in which the activity of specific cells in the nervous systems of fruit flies can be controlled using light. "The idea is to bioengineer ion channels that can be opened and closed with light flashes," Dickinson explains. "By controlling these genetically engineered ion channels, we can directly manipulate the electrical impulses that nervous systems use to sense and process information.

"This approach will allow us to study the function of specific cells and circuits in intact animals," Dickinson adds. Coinvestigator Ehud Isacoff of the University of California, Berkeley, will create these ion channels.

A fly might be engineered, for example, to begin flying or walking when pulsed with light of a certain wavelength. But this would be a means to a scientific goal and not the ultimate goal itself.

"This is one way of tapping into the fly and making cells do what we want them to do in order to test specific hypotheses about brain structure and behavior," Dickinson says. David Anderson, a coprincipal investigator and the Sperry Professor of Biology at Caltech, will work to place the light-controlled ion channels within as many unique cells in the flies' nervous systems as possible.

Prior work on the cellular basis of behavior has focused on how networks of brain cells may control simple behaviors such as swimming, flying, and feeding. The new work will probe these behaviors at a deeper level, attempting to figure out how nervous systems-and possibly even individual nervous-system cells-regulate simpler motor actions over time and space to generate more complex behaviors.

A central goal of the research will be to determine how a nervous system uses sensory data to process changes in a complex set of behaviors. Thus, the scientists will not only study the details of how the flies' sensory-based locomotion (walking and flying) works, but how their locomotion is related to crucial survival activities such as looking for food, seeking mates, laying eggs, searching for shelter, and getting out of harm's way.

"We will begin with the assumption that an animal's own natural behavior is the best context in which to interpret how its nervous system is built," Dickinson says. "The first step is to gather quantitative behavioral information concerning the external and internal cues that cause flies to change or modulate what they are doing.

"The next step is to gain experimental access to the specific cells that control these behavioral transitions, so we will develop genetically engineered flies that allow us to control the neurons that send information from the sensory areas of the brain to the circuits that generate and control movement. We will also study how gene expression controls and alters brain wiring.

"Collectively, this may help unravel one of the central questions in neuroscience: how brains regulate behavioral transitions."

Additional information on this and related grants is at http://www.nsf.gov/news/news_summ.jsp?cntn_id=108068&org=NSF&from=news

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Caltech Gets $18 Million from NHGRI to Map Vertebrate Development

PASADENA, Calif.—The National Human Genome Research Institute (NHGRI), a component of the National Institutes of Health (NIH), has awarded an $18-million grant for creation of a Center of Excellence in Genomic Science at the California Institute of Technology.

According to Marianne Bronner-Fraser, the Ruddock Professor of Biology at Caltech and principal investigator of the five-year program, the goal will be to image and mutate every developmentally important gene in vertebrates—that is, animals with backbones.

The work will be performed together with co-investigators Sean Megason and Scott Fraser from the Division of Biology, and Niles Pierce, an assistant professor of applied and computational mathematics and bioengineering.

"We will combine real-time analysis of gene expression on a genome-wide scale with the ability to mutate genes of interest," Bronner-Fraser says.

Initially, the research team will focus on the zebrafish, which is ideal for this type of work because of its transparent embryo and its rapid development.

"Our goal is to create the 'digital fish,'" Megason says. "This will be a computer model of the genetic orchestra that transforms an egg into an embryo."

"There will be an enormous payoff in new information about how development works at the genomic level," Bronner-Fraser adds.

The researchers will use new "in toto" imaging and genetic tagging tools invented by Megason and Fraser and new molecular detection methods being developed in the Pierce lab to analyze gene expression and function in the developing embryos. They will digitize this molecular data on a genomic scale by capturing thousands of time-lapse videos as the animals develop.

Once the approach is worked out on zebrafish, it will also be applied to the Japanese quail to make a "digital bird," because bird embryos develop in a fashion very similar to human embryos.

The Caltech grant is part of a $54-million grant portfolio awarded by the NHGRI for funding interdisciplinary work in genomic research. The NHGRI is best known for spearheading the Human Genome Project, which completely mapped the genetic blueprint of humans.

Now that the sequence of the genome for humans and many other species has been determined, the challenge ahead is to figure out how the genome functions during development and disease which is the goal of the CEGS (Center for Excellence in Genomic Science) program.

"The CEGS program is vital to our efforts to apply innovative genomic tools and technologies to the study of human biology," said NHGRI Director Francis S. Collins. "By fostering collaboration among researchers from many different disciplines, NHGRI aims to encourage innovation and build a powerful new framework for exploring human health and disease."

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Meyerowitz and Lange Awarded Balzan Prize

PASADENA, Calif.- California Institute of Technology faculty Andrew Lange and Elliot Meyerowitz have been named Balzan Prizewinners for 2006 by the International Balzan Foundation. Lange, Goldberger Professor of Physics, will share his award for observational astronomy and astrophysics with Paolo de Bernardis of Università di Roma La Sapienza in Italy "...for their contributions to cosmology, in particular the "BOOMERanG" Antarctic balloon experiment."

Lange and Italian team leader de Bernardis led the international team that developed BOOMERanG (Balloon Observations of Millimetric Extragalactic Radiation and Geophysics), a balloon-borne telescope capable of obtaining images of the universe in its embyronic state, long before the first stars formed. The images obtained in 1998, during a 10-day circumnavigation of Antarctica, revealed that the geometry of the universe is flat, and provided compelling evidence that 95 percent of the universe consists of exotic forms of matter and energy that remain largely a mystery.

Meyerowitz, Beadle Professor of Biology and biology division chair, will share his award for plant molecular genetics with Chris R. Somerville of Stanford University "...for their joint efforts in establishing Arabidopsis as a model organism for plant molecular genetics. This has far-reaching implications for plant science, both on a fundamental level and in potential applications."

Meyerowitz's primary research interest is the genes that control the formation of flowers, how altering these genes will affect flower development; and using computational models to study how plants grow. His laboratory has identified mutations that cause petal cells to develop into stamens instead, and another mutation that causes these same embryonic petals to become sepals. They and their collaborators have also produced computer models that faithfully reproduce the cellular behavior of meristems, the growing tips of shoots.

The winners named will be presented with their Balzan (pronounced bal-ZAHN) Prizes personally by the president of the Italian Republic, Giorgio Napolitano, during an award ceremony November 24 at the Accademia Nazionale dei Lincei, in the Palazzo Corsini in Rome. Each prize is worth one million Swiss francs, about $810,000 US. Because both Lange and Meyerowitz share their prizes with one other person, they will each receive half of the total, or about $405,000 US. Half of the prize money is awarded directly to the prizewinners in recognition of their outstanding scholarly work and they are asked to spend the other half on research projects carried out by young scholars or scientists in their respective fields.

The recipients were chosen by the General Prize Committee, a body chaired by Ambassador Sergio Romano and composed of 20 members representing European cultural institutions, from the candidates nominated by universities, academies, and cultural institutions throughout the world.

Unlike other international forms of recognition, the Balzan Prizes are awarded for different subjects each year, which are chosen annually by the Balzan Foundation. Two prizes are awarded in the humanities (literature, the moral sciences, and the arts) and two in the sciences (medicine and the physical, mathematical, and natural sciences). By rotating subjects, it is possible for the foundation to give preference to new or emerging areas of research, and to sustain important fields of study that may have been previously overlooked.

Additional recipients this year are Ludwig Finscher of the University of Heidelberg, Germany, for history of Western music since 1600, and Quentin Skinner of University of Cambridge, UK, for political thought: history and theory.

In 2007, Balzan Prizes will be awarded in European literature (1000-1500), international law since 1945, innate immunity, and nanoscience. The Prize for Humanity, Peace, and Brotherhood among Peoples will also be awarded next year; past winners include Mother Teresa and the International Committee of the Red Cross.

The International Balzan Foundation was founded in 1961 to promote the worthy causes of culture, the sciences and humanities, and peace and brotherhood in the world. The main concern of the foundation is to award the Balzan Prizes, which are given annually to individuals who have earned international distinction in their field, regardless of their nationality, race, or creed. At intervals of not less than three years, the Balzan Foundation also awards the Prize for Humanity, Peace, and Brotherhood among Peoples, which is worth two million Swiss francs. The Balzan Foundation operates on an international level through its two offices, which are legally distinct bodies: its Milan, Italy, headquarters is concerned with awarding the prizes, while the estate of Eugenio Balzan, which funds the Balzan Prizes, is managed from Zurich, Switzerland.

For details, see the Balzan Foundation website: http://www.balzan.it/default_eng.aspx. ### Contact: Jill Perry (626) 395-3226 jperry@caltech.edu Visit the Caltech Media Relations website at http://pr.caltech.edu/media.

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Structural Biologists Get First Picture of Complete Bacterial Flagellar Motor

PASADENA, Calif.-When it comes to tiny motors, the flagella used by bacteria to get around their microscopic worlds are hard to beat. Composed of several tens of different types of protein, a flagellum (that's the singular) rotates about in much the same way that a rope would spin if mounted in the chuck of an electric drill, but at much higher speeds-about 300 revolutions per second.

Biologists at the California Institute of Technology have now succeeded for the first time in obtaining a three-dimensional image of the complete flagellum assembly using a new technology called electron cryotomography. Reporting in Nature, the scientists show in unprecedented detail both the rotor of the flagellum and the stator, or protein assembly that not only attaches the rotor to the cell wall, but also generates the torque that serves to rotate it.

The accomplishment is a tour de force within the field of structural biology, through which scientists seek to understand how cells work by determining the shapes and configurations of the proteins that make them up. The results could lead to better-designed nanomachines.

"Rotors have been isolated and studied in detail," explains lead author Grant Jensen, an assistant professor of biology at Caltech. "But in the past, researchers have been forced to break the motor into pieces and/or rip it out of the cell before they could observe it in the microscope. It was like trying to understand a car engine by looking through salvaged parts. Here we were able to see the whole motor intact, like an engine still under the hood and attached to the drive train."

In terms of basic science, Jensen says, the motor is intrinsically interesting because it is such a marvelous and complex "nanomachine." But the results of studying it may also one day help engineers, who might want to use its structure to design useful things.

"The process of taking science to practical applications goes from the observation of interesting phenomena, to mechanistic understanding, to exploitation," Jensen says. "Right now, we're somewhere between observation and the beginning of mechanistic understanding of this wonderful motor."

The bacterium used in the study was isolated from the hindguts of termites. Although beneficial to the termite host, the bacterium, belonging to a group of organisms known as spirochetes, is closely related to the causative agents of syphilis, Lyme disease, and several organisms thought to play a role in gum disease. In all these cases, swimming motility is implicated as a possible determinant in disease.

The article is titled "In situ structure of the complete Treponema primitia flagellar motor." It is available as an advanced online publication of Nature at http://www.nature.com/nature/journal/vaop/ncurrent/full/nature05015.html.

The other authors are Gavin Murphy, a Caltech graduate student in biochemistry and molecular biophysics, and Jared R. Leadbetter, an associate professor of environmental microbiology at Caltech.

Photo caption: This image shows the three-dimensional reconstruction of the bacterial flagellar motor, as generated by electron cryotomography for the study. The rotor in the center (red) revolves at speeds of up to 300 times per second, driven by the stator assembly (yellow) that is embedded in the cell wall.

Photo by the authors (Gavin Murphy, Jared Leadbetter, and Grant Jensen, Caltech)

 

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Moore Foundation Gives $5.6 Million to Caltech for New Center to Study Cell Regulation

PASADENA, Calif.—The Gordon and Betty Moore Foundation has awarded $5.6 million to the California Institute of Technology for the creation of the Center for Integrative Study of Cell Regulation. The goal of the center is to develop new computational methods for understanding how the many genes and proteins that make up individual cells work together to carry out specialized functions of different cell types, including neurons, plant cells, and bacteria.

According to Mary Kennedy, the founding director and Davis Professor of Biology at Caltech, the center will merge Caltech's existing expertise in computation and in cell biology for the pursuit of new knowledge in the biological sciences. "We've reached a turning point where the sequencing of genomes has led to identification of all the genes and proteins of several organisms, and we are now ready to put the pieces together," she explains.

Kennedy says that due to the sheer complexity and volume of information to be handled, application of advanced computational methods and significant computational power is important for further progress. Therefore, the types of problems the center scientists and engineers will work on will include development of algorithms for identifying, locating, and determining the shape and orientation of key proteins in high-resolution cryo-electron microscopic images of cells, and creation of computer programs to simulate complex biochemical signaling pathways in neuronal synapses.

Center personnel will help to develop methods for following the movement of individual cells within a developing embryo in a series of microscopic images and will construct new database architectures for organizing existing data about gene sequences so that comparisons can be made among similar genes in various species.

In short, the center will advance cell biology by introducing new computational methods that haven't previously been widely applied in the life sciences, Kennedy says.

The initial projects will include the modeling of spatial organization, assembly, and function of bacteria and viruses, led by Grant Jensen, an assistant professor of biology at Caltech; the modeling of biochemical mechanisms in brain synapses to better understand the chemistry of learning and memory, led by Kennedy; and the modeling of cell and tissue structure and gene expression during plant development, led by Elliot Meyerowitz, Caltech's division chair of biology.

Marianne Bronner-Fraser, Caltech's Ruddock Professor of Biology, will be involved in the development of a database for uncovering patterns in closely related organisms to better understand the functioning of genes in the evolutionary tree.

The codirector of the center will be Mark Stalzer, who is the executive director of the Center for Advanced Computing Research (CACR) at Caltech. Three or four additional CACR personnel will also be involved in the application of computational methods and programming to problems in integrative cell biology.

During its initial five years of grant funding, the center will help to support the research of about five to ten laboratories in Caltech's Division of Biology and in CACR, which is housed in the Division of Engineering and Applied Science. Other divisions may also be involved as the work progresses.

According to Kennedy, Caltech is in a unique position to create such a center because of its decades-old commitment to close interdisciplinary work among its faculty and research groups, and also because of its longstanding tradition of approaching biological research at the most fundamental levels.

"The future of biology is in the complex level of understanding that must be approached quantitatively, and with the aid of state-of-the-art computers," she says. "So this is a natural change in paradigms."

Established in September 2000, the Gordon and Betty Moore Foundation seeks to develop outcome-based projects that will improve the quality of life for future generations. It has organized the majority of its grant making around large-scale initiatives. It concentrates funding in three program areas: environmental conservation, science, and the San Francisco Bay Area.

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Robert Tindol
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New Drugs for Smoking Cessation to Be the Target of Grant-Funded Partnership

PASADENA, Calif.—The California Institute of Technology has been awarded a five-year grant for $4.6 million from the National Institute on Drug Abuse to develop a program for discovering medications aimed either at helping people avoid nicotine addiction or at helping smokers to quit. The project will include researchers from the University of Colorado at Boulder and from Targacept, a North Carolina-based biopharmaceutical company whose scientists are leaders in research focused on a class of receptors known as neuronal nicotinic receptors.

Henry Lester, Caltech's Bren Professor of Biology and presently chair of the Caltech faculty, is directing the project, which is called a "National Cooperative Drug Discovery Group in Smoking Cessation." Lester's group will develop new strains of mice, each exaggerating the action of a particular nicotinic receptor subtype. The researchers plan to define the behavior of the mice, and of nerve cells in these mice, as they respond to nicotine and to candidate smoking-cessation drugs.

Lester's group has already established a track record in the study of nicotine addiction. In November 2004, the Caltech and Boulder groups published an article in Science announcing experimental results with "knock-in" mice, whose receptors had been genetically engineered for hypersensitivity to nicotine. The results indicated that specific drug interventions for addressing nicotine addiction were, in principle, very possible to design.

Special mice provide a fruitful way to go about the design of new drugs because an experimental animal designed for hypersensitivity to nicotine is appropriate for tracking nicotine-dependent molecular signals within the nervous system. A goal is to find ways to block one or more of these signals to interfere with the release of dopamine, which has long been associated with pleasure and contentment. Another goal is to interfere with the molecular changes that constitute addiction itself. With the accomplishment of these goals, smoking might never become an irresistible, pleasurable habit.

"I personally believe that nicotine addiction will be among the first addictions to be solved, because we already have so many tools to study it," Lester said in 2004 after the Science paper was published.

In the new research program, the Lester group will provide "target selection" by identifying the most promising strategies for developing drugs. The Boulder group, led by Michael Marks, will conduct discovery and optimization phases by applying sophisticated biochemical measurements to the mice, further describing the response to individual drugs.

Targacept's efforts will be led by Merouane Bencherif. Targacept will identify from its compound portfolio candidate drugs that interact selectively with the applicable nicotinic receptor subtypes. Targacept designs, discovers, and develops novel compounds that act upon various subtypes to promote therapeutic effects and to limit adverse side effects. In addition to the new project in smoking cessation, Targacept's therapeutic focus is on central-nervous-system diseases and disorders such as Alzheimer's disease and other cognitive disorders, along with schizophrenia, pain, depression, and anxiety.

The National Cooperative Drug Discovery Group brings together the complementary talents of these groups to define useful approaches to smoking cessation. Advisors to the group include William Corrigall, who first proved that nicotine is addictive in animals; Allan Collins of Boulder, an expert on the genetics of nicotine and alcohol addiction; and Dennis Dougherty, Caltech's Hoag Professor of Chemistry, who has worked with Lester for years on the chemistry of neuroreceptors.

Although many complex steps occur between primary research and clinical use of a drug, the researchers hope that by studying the biology of nicotinic receptors, the compounds that act on these receptors, and their effect upon stylized animal behaviors that resemble addiction, they will define new principles applicable to smoking cessation and facilitate the development of effective new therapies.

The National Institute on Drug Abuse is part of the National Institutes of Health.

 

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Robert Tindol
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Caltech and UC San Diego School of Medicine Create Program to Train Academic Physicians

PASADENA and SAN DIEGO, Calif.—High-school seniors looking for a futuristic way of studying medicine may want to take note. Beginning next year, six newly admitted freshmen at the California Institute of Technology will also be offered early admission to the University of California, San Diego, (UCSD) School of Medicine, pending completion of their Caltech degrees as "medical scholars."

The launch of this new program corresponds with a new report released by the Association of American Medical Colleges (AAMC) advocating stepped-up efforts to educate clinician-researchers who are able to "propel scientific advances into better diagnostics, treatments and preventatives of disease" ("Promoting Translational and Clinical Science: The Critical Role of Medical Schools and Teaching Hospitals," released by the AAMC Task Force II on Clinical Research, can be found online at www.aamc.org/promotingclinicalscience)

According to David Baltimore, president of Caltech, the new program will allow the institute to "tap into an elite pool of students" and to be more directly involved in the training of physicians with especially strong backgrounds in research.

"Many of our top students with interests in biology, bioengineering, biophysics, and chemistry have always intended to apply to medical school once they leave Caltech," said Baltimore. "This joint program with UCSD will allow the two institutions to select an outstanding group of students who are at the top academically and are committed to helping others."

"This partnership with Caltech will help us identify promising individuals with the potential to become leaders and innovators in medicine and life sciences. This will help fill the need for physicians who can not only deliver care, but improve health through basic and clinical research," said Marye Anne Fox, chancellor of UC San Diego.

The first students admitted to the program in the fall of 2007 will be selected through the undergraduate admissions process at Caltech and will be further screened by the UCSD School of Medicine. Typical medical scholars will have been involved in biomedical research and/or clinical endeavors at the high-school level and, like all other students at Caltech and the UCSD School of Medicine, will have excellent grades and test scores.

Once the medical scholars have graduated from Caltech, they will matriculate at the UCSD School of Medicine, provided they have maintained good academic standing. Any Caltech major will be acceptable for matriculation at the medical school.

During the students' undergraduate years at Caltech, UCSD faculty will be involved in programs of special seminars and lectures that will introduce them to a range of subjects that are part of the medical-school experience.

Paul Patterson, the Biaggini Professor of Biological Sciences at Caltech, says the new program will serve two large purposes. "We think it will give us access to the very high-quality pool of biology undergraduates who may currently be going elsewhere because they think Caltech is too difficult or too oriented toward the physical sciences," he said.

"But also, the training will be different from the standard training premeds get at other schools because of the rigorous undergraduate program in the physical sciences and mathematics, and the wide opportunities here for research. So this will be good for medical research as well."

Judith Swain, MD, dean for translational medicine at the UC San Diego School of Medicine, echoes these comments. The program is modeled after UCSD's Medical Scholars Program, which identifies 12 first-year undergraduates at UC San Diego who are guaranteed admission to the UCSD medical school provided they maintain good academic standing and have competitive grades and test scores.

"By getting to these students early and introducing them to the broad variety of careers available to them in medicine and research, we cultivate a strong pool of individuals interested in becoming basic and clinical researchers, innovative clinicians, scholars, and teachers-tomorrow's medical leaders," she said.

"These are the type of people who contribute to our understanding of the pathological and genetic basis of disease and go on to develop new treatments and diagnostic technologies. In addition, having this opportunity to matriculate outstanding students who will have completed Caltech's science and mathematics curriculum will enrich our medical school's student body."

"Our experience at UCSD is that the Medical Scholars Program allows students the opportunity to explore scholarly pursuits without the anxieties so many premedical students have about restricting their curricular and extracurricular activities to those thought to be most appealing to medical-school admissions committees," added Carolyn Kelly, MD, associate dean for admissions and student affairs, UCSD School of Medicine.

 

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Robert Tindol
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