Sarkis Mazmanian Discusses Benevolent Bacteria in Scientific American

There are trillions of bacteria living in our bodies, making up complex communities of microbes regulating processes like digestion and immunity. For Caltech biologist Sarkis Mazmanian, they also make up the focus of his research: understanding how the "good" bacteria promote human health. Featured in the cover story for the June issue of Scientific American, he makes a case for devoting more attention to the helpful bugs after years of scientific dedication to pathogens. "It goes against dogma to think that bacteria would make our immune systems function better," he says, in the article. "But the picture is getting very clear: the driving force behind the features of the immune system are commensals."

The magazine is available now on newsstands and the article, "The Ultimate Social Network," can be read online with a subscription.

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Decoding Worm Lingo

Caltech biologists discover that many nematode species make the same types of small-molecule pheromones

PASADENA, Calif.—All animals seem to have ways of exchanging information—monkeys vocalize complex messages, ants create scent trails to food, and fireflies light up their bellies to attract mates. Yet, despite the fact that nematodes, or roundworms, are among the most abundant animals on the planet, little is known about the way they network. Now, research led by California Institute of Technology (Caltech) biologists has shown that a wide range of nematodes communicate using a recently discovered class of chemical cues.

A paper outlining their studies—which were a collaborative effort with the laboratory of Frank C. Schroeder, assistant scientist at the Boyce Thompson Institute for Plant Research (BTI) of Cornell University—was published online April 12 in the journal Current Biology

Previous research by several members of this team had recently shown that a much-studied nematode, Caenorhabditis elegans, uses certain chemical signals to trade data. What was unknown was whether other worms of the same phylum "talk" to one another in similar ways.

But when the researchers looked at a variety of nematodes, they found the very same types of chemicals being combined and used for communication, says Paul Sternberg, the Thomas Hunt Morgan Professor of Biology at Caltech and senior author on the study. "It really does look like we've stumbled upon the letters or words of a universal nematode language, the syntax of which we don't yet fully understand," he says.

Nematodes are wide-ranging creatures; they have been found in hot springs, arctic ice, and deep-sea sediments. Many types of nematodes are harmless, or even beneficial, but others cause damage to plants and harm to humans and animals. Decoding the language of these worms could allow us to develop strategies to prevent the spread of unwanted nematode species, saving time and money for the agricultural and health-care industries.

"We can now say that many—maybe all—nematodes are communicating by secreting small molecules to build chemical structures called ascarosides," says Sternberg, whose past research in C. elegans found that those worms secrete ascarosides both as a sexual attractant and as a way to control the social behavior of aggregation. "It's really exciting and a big breakthrough that tells us what to look for and how we, too, might be able to communicate with this entire phylum of animals." 

Building upon Sternberg's previous findings, he and Andrea Choe, then a graduate student and now a postdoctoral scholar in biology at Caltech, decided to look for evidence of ascarosides in other species of nematodes. These included some parasitic organisms as well as some benign roundworm samples.

"I turned a section of Paul's lab into a parasite zoo, and people were both intrigued by it and terrified to come back there," says Choe. "One day they would see me cutting carrots to culture plant parasites, and the next I would be infecting mosquitoes or harvesting hookworms from rat intestines. We really tried to get as many different samples as we could."

Once they had cultured a sufficient number of different nematode species, the creatures were bathed in a liquid solution dubbed "worm water." This worm water collected the chemicals given off by the nematodes. The worms were then filtered out and sent to Schroeder's lab at BTI to be analyzed using a mass spectrometer—a tool used to deduce the chemical structure of molecules.

"When the results came back from BTI, showing that the same ascarosides were present in all the worm-water samples, I thought that they had made a mistake," says Choe. "It was a very surprising finding."

Using technology developed by Dima Kogan, a former graduate student at Caltech and coauthor of the paper, the researchers were also able to test the responses of various worms to particular ascarosides. Worms were placed on an agar plate, along with an experimental cue—a blend of ascarosides. Any action that might occur on the plates was then recorded; Kogan's software analyzed those recordings frame by frame, counting the number of worms that were either attracted or repelled by the given chemicals.

When asked about the development of the software, Choe explains that it all began when Kogan noticed that the current method involved counting worms by eye. "He was stunned that we would spend our time doing this," says Choe, "and he came up with this software in less than a week. It removed user bias, sped up our research 10-fold, and allowed us to study more chemicals and more species."

Next, the researchers will work to learn more about how the worms actually sense the ascarosides.

"Now that we know these chemicals are broadly present in nematodes, we want to find the genes that are responsible for the ability to respond to these chemicals," says Sternberg, who is also an investigator with the Howard Hughes Medical Institute. "That knowledge could open up a whole other angle, not just for dealing with the chemicals, but for actually interfering with those communication systems a little downstream by hitting the receivers."

The team also plans to continue deconstructing the language they have found among nematodes. For example, Sternberg wonders, how many different combinations of chemicals mean "food," or "mate," or "attack"? If the scientists can crack the code in terms of what different blends mean to different species, they can begin to interfere with the actions of the nematodes that wreak havoc across the world—leading to better eradication of plant pests, as well as human and animal parasites.

"There is only one known worm pheromone used in agriculture," says Choe. "It is time for us change that. This research could be a very big breakthrough on that front."

The Current Biology study, "Ascaroside Signaling is Widely Conserved Among Nematodes," was funded by a grant from the National Institutes of Health and was supported by the Howard Hughes Medical Institute. Additional authors on the study are Stephan H. von Reuss, from Schroeder's lab at BTI; Robin B. Gasser, from the University of Melbourne; and Edward G. Platzer, from UC Riverside.

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Determining a Stem Cell's Fate

Caltech biologists scour mouse genome for genes and markers that lead to T cells

PASADENA, Calif.—What happens to a stem cell at the molecular level that causes it to become one type of cell rather than another? At what point is it committed to that cell fate, and how does it become committed? The answers to these questions have been largely unknown. But now, in studies that mark a major step forward in our understanding of stem cells' fates, a team of researchers from the California Institute of Technology (Caltech) has traced the stepwise developmental process that ensures certain stem cells will become T cells—cells of the immune system that help destroy invading pathogens.

"This is the first time that a natural developmental process has been dissected in such detail, going from step to step to step, looking at activities of all the genes in the genome," says Ellen Rothenberg, the principal investigator on the study and Albert Billings Ruddock Professor of Biology at Caltech. "It means that in genetic terms, there is virtually nothing left hidden in this system."

The study was led by Jingli A. Zhang, a graduate student in Rothenberg's lab, who is now a postdoctoral scholar at Caltech. The group's findings appear in the April 13 issue of the journal Cell.

The researchers studied multipotent hematopoietic precursor cells—stem-cell-like cells that express a wide variety of genes and have the capability to differentiate into a number of different blood-cell types, including those of the immune system. Taking into consideration the entire mouse genome, the researchers pinpointed all the genes that play a role in transforming such precursor cells into committed T cells and identified when in the developmental process they each turn on.  At the same time, the researchers tracked genes that could guide the precursor cells to various alternative pathways.  The results showed not only when but also how the T-cell-development process turned off the genes promoting alternative fates.

"We were able to ask, 'Do T-cell genes turn on before the genes that promote some specific alternative to T cells turn off, or does it go in the other order? Which genes turn on first? Which genes turn off first?'" Rothenberg explains. "In most genome-wide studies, you rarely have the ability to see what comes first, second, third, and so on, in a developmental progression. And establishing those before-after relationships is absolutely critical if you want to understand such a complicated process."

The researchers studied five stages in the cascade of molecular events that yields a T cell—two before commitment, a commitment stage, and then two following commitment. They identified the genes that are expressed throughout those stages, including many that code for regulatory proteins, called transcription factors, which turn particular genes on or off. They found that a major regulatory shift occurs between the second and third stages, when T-cell commitment sets in. At that point, a large number of the transcription factors that activate genes associated with uncommitted stem cells turn off, while others that activate genes needed for future steps in T-cell development turn on.

The researchers looked not only at which genes are expressed during the various stages but also at what makes it possible for those genes to be expressed at that particular time. One critical component of regulation is the expression of transcription-factor genes themselves. Beyond that, the researchers were interested in identifying control sequences—the parts of genes that serve as docking sites for transcription factors. These sequences are often very difficult to identify in mice and humans using classical molecular-biology techniques; scientists have spent as many as 10 years trying to create a comprehensive map of the control sequences for a single gene. 

To create a map of likely control sequences, Zhang studied epigenetic markers. These are chemical modifications, such as those that change the way the DNA is bundled. They become associated with particular regions of DNA as a result of the action of transcription factors and can thereby affect how easy or hard it is for a neighboring gene to be turned on or off. By identifying DNA regions where epigenetic markers are added or removed, Rothenberg's group has paved the way for researchers to identify control sequences for many of the genes that turn on or off during T-cell development.

In some ways, Rothenberg says, her team is taking a backward approach to the problem of locating these control sequences. "What we're saying is, if we can tell that a gene is turned on at a certain point in terms of producing RNA, then we should also be able to look at the DNA sequences right around it and ask, 'Is there any stretch of DNA sequence that adds or loses epigenetic markers at the same time?'" Rothenberg says. "If we find it, that can be a really hot candidate for the control sequences that were used to turn that gene on." 

Two methodologies have made it possible to complete this work. First, ultra-high-throughput DNA sequencing was used to identify when major changes in gene expression occur along the developmental pathway. This technique amplifies DNA sequences taken throughout millions of cell samples, puts all of the bits in order, compares them to the known genome sequence (for mice, in this case), and identifies which of the various genes are enriched, or found in greater numbers. Those that are enriched are the ones most likely to be expressed. The team also used a modified version of this sequencing technique to identify the parts of the genome that are associated with particular epigenetic markers. Coauthor Barbara Wold, Caltech's Bren Professor of Molecular Biology, is an expert in these so-called "next-generation" deep-sequencing technologies and provided critical inspiration for the study.

A second important methodology involved an in vitro tissue-culture system developed in the lab of Juan Carlos Zúñiga-Pflücker of the University of Toronto, which enabled the Caltech researchers to mass-produce synchronized early T-cell precursors and to see the effect of altered conditions on individual cells in terms of producing T cells or other cells.

Zhang is lead author of the paper in Cell, titled "Dynamic transformations of genome-wide epigenetic marking and transcriptional control establish T cell identity." In addition to Zhang, Rothenberg, and Wold, Brian Williams, a senior scientific researcher at Caltech, was also a coauthor. Another coauthor, developmental biologist Ali Mortazavi, was part of Wold's lab and was also associated with the lab of Paul Sternberg when the work was completed; he is now an assistant professor at the University of California, Irvine.

The work was supported by the Beckman Institute, the Millard and Muriel Jacobs Genetics and Genomics Laboratory, the L.A. Garfinkle Memorial Laboratory Fund, the Al Sherman Foundation, the Bren Professorship, the A.B. Ruddock Professorship, and grants from the National Institutes of Health.

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Alexander Varshavsky Awarded Otto Warburg Medal

Alexander Varshavsky, Caltech's Howard and Gwen Laurie Smits Professor of Cell Biology, has been awarded the Otto Warburg Medal of the German Society for Biochemistry and Molecular Biology (GBM). The medal is considered to be the highest German award for biochemists and molecular biologists.

Varshavsky's main recognized contribution was the fundamental discovery, in the 1980s, of biological regulation by intracellular protein degradation and its central importance in cellular physiology. This discovery by the Varshavsky laboratory involved the understanding, through genetic and biochemical insights, of the biological functions of the ubiquitin system, a major proteolytic circuit in living cells. Ubiquitin is a small protein that is present in cells either as a free protein or as a part of complexes with many other proteins. The association of ubiquitin with cellular proteins marks them for degradation or other metabolic fates. Through its ability to destroy specific proteins, the ubiquitin system plays a major role in cell growth and differentiation, DNA repair, regulation of gene expression, and many other biological processes.

"Alexander Varshavsky's research on ubiquitin-dependent intracellular protein degradation has revolutionised that area of research," Professor Irmgard Sinning, president of GBM, said in the citation. "We owe to him a series of discoveries with a tremendous impact on cell biology and helping us to better understand and study numerous diseases."

The recipient of numerous awards, including most recently the 2012 King Faisal International Prize for Science, Varshavsky earned his BS from Moscow State University in 1970 and his PhD from the Institute of Molecular Biology in 1973. He has been Smits Professor at Caltech since 1992.

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Do You Hear What I Hear?

Caltech biologists locate brain's processing point for acoustic signals essential to human communication

PASADENA, Calif.—In both animals and humans, vocal signals used for communication contain a wide array of different sounds that are determined by the vibrational frequencies of vocal cords. For example, the pitch of someone's voice, and how it changes as they are speaking, depends on a complex series of varying frequencies. Knowing how the brain sorts out these different frequencies—which are called frequency-modulated (FM) sweeps—is believed to be essential to understanding many hearing-related behaviors, like speech. Now, a pair of biologists at the California Institute of Technology (Caltech) has identified how and where the brain processes this type of sound signal.

Their findings are outlined in a paper published in the March 8 issue of the journal Neuron.

Knowing the direction of an FM sweep—if it is rising or falling, for example—and decoding its meaning, is important in every language. The significance of the direction of an FM sweep is most evident in tone languages such as Mandarin Chinese, in which rising or dipping frequencies within a single syllable can change the meaning of a word.

In their paper, the researchers pinpointed the brain region in rats where the task of sorting FM sweeps begins.

"This type of processing is very important for understanding language and speech in humans," says Guangying Wu, principal investigator of the study and a Broad Senior Research Fellow in Brain Circuitry at Caltech. "There are some people who have deficits in processing this kind of changing frequency; they experience difficulty in reading and learning language, and in perceiving the emotional states of speakers. Our research might help us understand these types of disorders, and may give some clues for future therapeutic designs or designs for prostheses like hearing implants."

The researchers—including co-author Richard I. Kuo, a research technician in Wu's laboratory at the time of the study (now a graduate student at the University of Edinburg)—found that the processing of FM sweeps begins in the midbrain, an area located below the cerebral cortex near the center of the brain—which, Wu says, was actually a surprise.

"Some people thought this type of sorting happened in a different region, for example in the auditory nerve or in the brain stem," says Wu. "Others argued that it might happen in the cortex or thalamus. "

To acquire high-quality in-vivo measurements in the midbrain, which is located deep within the brain, the team designed a novel technique using two paired—or co-axial—electrodes. Previously, it had been very difficult for scientists to acquire recordings in hard-to-access brain regions such as the midbrain, thalamus, and brain stem, says Wu, who believes the new method will be applicable to a wide range of deep-brain research studies.

In addition to finding the site where FM sweep selectivity begins, the researchers discovered how auditory neurons in the midbrain respond to these frequency changes. Combining physical measurements with computational models confirmed that the recorded neurons were able to selectively respond to FM sweeps based on their directions. For example, some neurons were more sensitive to upward sweeps, while others responded more to downward sweeps.

"Our findings suggest that neural networks in the midbrain can convert from non-selective neurons that process all sounds to direction-selective neurons that help us give meanings to words based on how they are spoken. That's a very fundamental process," says Wu.  

Wu says he plans to continue this line of research, with an eye—or ear—toward helping people with hearing-related disorders. "We might be able to target this area of the midbrain for treatment in the near future," he says.

The Neuron study, "The Generation of Direction Selectivity in the Auditory System," was funded by grants from the Broad Fellows Program in Brain Circuitry of the Broad Foundation and Caltech.

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Understanding Bacterial Sensors

Researchers Piece Together Model of Chemoreceptor Arrays

Nearly all motile bacteria can sense and respond to their surroundings—finding food, avoiding poisons, and targeting cells to infect, for example—through a process called chemotaxis. This allows the bacteria to move towards chemicals they are attracted to, and away from ones that repel them. Because chemotaxis plays a critical role in the first steps of bacterial infection, a better understanding of the process could pave the way for the development of new, more effective antibiotics. Researchers at Caltech are helping to reveal just how chemotaxis works.

In bacteria, the sensing process begins with chemoreceptors—proteins that extend, like tiny antennae, from the cell body to the exterior of the cell. Chemoreceptors bind to attractants, like sugars and amino acids, and to repellents, like metals; they then send signals to motors controlling the whiplike flagella that steer the swimming bacterium in a particular direction.

In an effort to better understand chemotaxis, Grant Jensen, a professor of biology at Caltech, has been working with research specialist Ariane Briegel to determine the exact arrangement of these exquisitely sensitive receptors. Using advanced electron microscopy techniques and new crystallography results, Jensen and Briegel, working with researchers from Cornell University, have built the first model that depicts precisely how chemoreceptors and the proteins around them are structured at the sensing tip of bacteria. Their results appeared recently in the Proceedings of the National Academy of Science (PNAS).

The entire chemotaxis system functions with about 11 proteins, making it one of the simplest examples of a signal transduction pathway (a system in which the activation of a receptor leads to any number of chemical steps that produce a specific response—in this case, a bacterium swimming in a particular direction). In humans, signaling pathways control everything from development and tissue repair to immunity and aspects of brain function; defects in such pathways produce diseases such as diabetes and cancer.  In animal cells, a signal transduction pathway might include 500 proteins. The relatively simple pathway producing the chemotaxis system, therefore, “is the best starting point to understand a full signal transduction pathway," Briegel says.

Brian Crane of Cornell University solved a new crystal structure (top) featuring a double ring of chemoreceptor fragments (pink and purple) and parts of CheA (black and blue) and CheW (green). Split into two (bottom), the receptor fragments in the crystal structure lined up perfectly with Briegel's ECT images.
Credit: Briegel et al./Caltech

In 2009, Jensen's group was able to get the first glimpse of the chemoreceptor architecture. To see it, the researchers used a state-of-the-art electron microscope, purchased by Caltech using a gift from the Gordon and Betty Moore Foundation, that enabled them to observe bacterial cell samples in a near-native state. Unlike traditional electron microscopy—for which samples must be fixed, embedded in plastic, sectioned, and stained—the new imaging technique, called electron cryotomography (ECT), involves freezing samples so quickly that they become trapped within a layer of transparent, glasslike ice. The microscope can then capture many high-resolution images as the sample is rotated.

With that first look, three years ago, Jensen and Briegel discovered that chemoreceptors are arranged in a regular, repeating lattice of hexagons that are 12 nanometers apart, center-to-center.

By rotating the model with two CheA proteins about part of the CheA pair,the team wound up with two connected rings (top) with the proteins and receptors in the same plane. The spacing between those rings explains the hexagonal lattice Jensen's group saw with ECT (middle and bottom).
Credit: Briegel et al./Caltech

But Jensen and Briegel knew they were not seeing the whole picture. Arriving at the complete model required a multistep effort. First, Briegel used improved sample preparation and data-processing procedures to generate even higher resolution images of the honeycomblike chemoreceptor arrays. These new higher-resolution pictures allowed her to determine the precise arrangement of the receptors in these arrays: she discovered that six chemoreceptors are located at each corner of each hexagon. The chemoreceptors are arranged in a pattern that scientists call "trimers of dimers"—that is, groups of three sets of two pairs of receptors. The trimers are arranged such that each pair points toward a center of a hexagon.

Biologists have long known that two additional proteins, called CheA and CheW, are also found within groups of chemoreceptors. These proteins were thought to hold the receptors together and to activate a protein that then binds to the flagellar motors and causes a change in its spinning direction. But no one knew exactly how CheA, CheW, and the receptors were linked.

Understanding that, Jensen says, is "a huge step forward."

For help with the next piece, Caltech researchers teamed up with Brian Crane of Cornell University, who then solved a crystal structure featuring a double ring of chemoreceptor fragments and parts of CheA and CheW. While viewing a computer model of the structure, the researchers realized that splitting the double ring into two and then lining up the receptor fragments in each ring with the receptors in Briegel's ECT images produced a perfect match.

CheA never works alone: it forms in pairs. The ring of Crane's crystal structure, however, only contained part of one CheA. So Crane's group used data from electron spin resonance (ESR) and crystallography experiments to build a model with two CheA proteins. The team discovered that simple rotations of part of the CheA pair brought all of the proteins and receptors into the same plane and produced two connected rings.

"The spacing between those rings explains the hexagonal lattice we see with ECT," says Briegel. "For the first time we have a very convincing model of how this whole receptor array is put together."

The group's next step is to determine what structural changes take place when an attractant binds to a chemoreceptor to send a signal to the flagella motors. Having a model for the whole receptor array, Jensen says, makes that task easier. "Seeing the arrays was one thing," he says. "Now, seeing the receptors with all the helper molecules and how they're arranged and linked together, we have a chance of understanding what happens when one of them gets activated."

Along with Briegel, Jensen, and Crane, additional authors on the PNAS paper, "Bacterial chemoreceptor arrays are hexagonally packed trimers of receptor dimers networked by rings of kinase and coupling proteins," are Xiaoxiao Li and Alexandrine Bilwes of Cornell, and Kelly Hughes of the University of Utah. The work was supported by the Howard Hughes Medical Institute and the National Institutes of Health.

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Some Bacteria Attack Using Spring-loaded Poison Daggers

PASADENA, Calif.—Bacteria have evolved different systems for secreting proteins into the fluid around them or into other cells. Some, for example, have syringe-like exterior structures that can pierce other cells and inject proteins. Another system, called a type VI secretion system, is found in about a quarter of all bacteria with two membranes. Despite being common, researchers have not understood how it works. Now a team, co-led by researchers at the California Institute of Technology (Caltech), has figured out the structure of the type VI secretion system apparatus and proposed how it might work—by shooting spring-loaded poison molecular daggers.

"People aren't surprised that animals have really interesting ways to hurt each other—snakes have venom, bears have claws," says Grant Jensen, professor of biology at Caltech and coleader of the study. "But they might be surprised that a single cell within one of those animals' bodies is still 100 times larger than the bacterial cells we're talking about, and yet the bacterial cells contain weapons that are so sophisticated. That's the marvel."

The nano-weapon—which spans a distance no longer than about 80 atoms lined up end-to-end—is a tube that contracts very quickly, firing an inner dagger through the cell's membranes, into the surrounding medium and, possibly, into another cell. The tube then disassembles and can reassemble elsewhere in the cell, ready to fire another molecular dagger.

The findings, made in collaboration with researchers at Harvard Medical School, appear as an advance online publication of the journal Nature.

The work began with an accidental discovery. Researchers in the Jensen lab were using an electron cryomicroscope—an electron microscope that enables researchers to observe samples in a near-native state—to image an environmental strain of Vibrio cholerae cells. Unlike traditional electron microscopy—for which samples must be fixed, dehydrated, embedded in plastic, sectioned, and stained—electron cryotomography (ECT) involves freezing samples so quickly that they become trapped within a layer of transparent, glasslike ice. The microscope can then capture high-resolution images as the sample is rotated, and those images can be stitched together to make 3D videos—so-called tomograms.

Jensen and his team wanted to use the technique to observe how V. cholerae cells segregate two duplicate copies of their genetic material before dividing. Instead, they noticed relatively large tubelike structures spanning the entire width of the cells. And they had no idea what the structures were. 

Jensen started sharing preliminary images of the mysterious structures in lectures around the country, asking if anyone knew what they might be. Finally, someone suggested that he talk to John Mekalanos of Harvard Medical School, who was involved in the original discovery of the type VI secretion system. 

The Mekalanos lab made a version of V. cholerae lacking one of the proteins that makes up the tube structure. With that protein knocked out, the type VI secretion system disappeared. In another experiment, they attached fluorescent tags to the proteins and were actually able to watch the structures form and contract within living cells.

"When the tube contracts, that's when it shoots," says Martin Pilhofer, a postdoctoral scholar in Jensen's lab. "That result agrees well with what we had seen using the electron cryomicroscope, where we observed long tubular structures in two different conformations—extended and contracted. Whereas electron cryomicroscopy allowed us to observe the secretion apparatus at high resolution, the fluorescence study gave us more insight into the dynamics of the system."

The firing mechanism is similar to the one used by bacteriophages, viruses that infect bacteria. Phage tails are made up of an outer sheath and an inner tube that gets ejected. Since other researchers had previously established that proteins in the type VI secretion system are similar to those found in various parts of the phage tail and its associated structures, there is even more support for the newly discovered mechanism for the type VI secretion system.

"These amazing tubes inside the cell went undetected for decades of traditional electron microscopy, and they may have stayed that way for many more," says Jensen, who is also an HHMI investigator. "But Caltech made a wise investment a long time ago, with the generous help of the Gordon and Betty Moore Foundation, into our one-of-a-kind electron cryomicroscope, and it is truly what allowed us to see these structures."

In addition to Jensen, Pilhofer, and Mekalanos, other authors on the Nature paper, "Type VI secretion requires a dynamic contractile phage tail-like structure," include Gregory Henderson, a former graduate student in Jensen's lab who is now a resident physician at the Mayo Clinic, and Marek Basler, a postdoctoral scholar at Harvard Medical School. The work was supported by grants from the National Institute of Allergy and Infectious Diseases and the National Institute of General Medical Sciences.

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Caltech Researchers Develop Gene Therapy to Boost Brain Repair for Demyelinating Diseases

PASADENA, Calif.—Our bodies are full of tiny superheroes—antibodies that fight foreign invaders, cells that regenerate, and structures that ensure our systems run smoothly. One such structure is myelin—a material that forms a protective, insulating cape around the axons of our nerve cells so that they can send signals quickly and efficiently. But myelin, and the specialized cells called oligodendrocytes that make it, become damaged in demyelinating diseases like multiple sclerosis (MS), leaving neurons without their myelin sheaths. As a consequence, the affected neurons can no longer communicate correctly and are prone to damage. Researchers from the California Institute of Technology (Caltech) now believe they have found a way to help the brain replace damaged oligodendrocytes and myelin.  

The therapy, which has been successful in promoting remyelination in a mouse model of MS, is outlined in a paper published February 8 in The Journal of Neuroscience.

"We've developed a gene therapy to stimulate production of new oligodendrocytes from stem and progenitor cells—both of which can become more specialized cell types—that are resident in the adult central nervous system," says Benjamin Deverman, a postdoctoral fellow in biology at Caltech and lead author of the paper. "In other words, we're using the brain's own progenitor cells as a way to boost repair."

The therapy uses leukemia inhibitory factor (LIF), a naturally occurring protein that was known to promote the self-renewal of neural stem cells and to reduce immune-cell attacks to myelin in other MS mouse models.

"What hadn't been done before our study was to use gene therapy in the brain to stimulate these cells to remyelinate," says Paul Patterson, the Biaggini Professor of Biological Sciences at Caltech and senior author of the study.

According to the researchers, LIF enables remyelination by stimulating oligodendrocyte progenitor cells to proliferate and make new oligodendrocytes. The brain has the capacity to produce oligodendrocytes, but often fails to prompt a high enough repair response after demyelination.

"Researchers had been skeptical that a single factor could lead to remyelination of damaged cells," says Deverman. "It was thought that you could use factors to stimulate the division and expansion of the progenitor population, and then add additional factors to direct those progenitors to turn into the mature myelin-forming cells. But in our mouse model, when we give our LIF therapy, it both stimulates the proliferation of the progenitor cells and allows them to differentiate into mature oligodendrocytes."  

In other words, once the researchers stimulated the proliferation of the progenitor cells, it appeared that the progenitors knew just what was needed—the team did not have to instruct the cells at each stage of development. And they found that LIF elicited such a strong response that the treated brain's levels of myelin-producing oligodendrocytes were restored to those found in healthy populations.

The researchers note, too, that by placing LIF directly in the brain, one avoids potential side effects of the treatment that may arise when the therapy is infused into the bloodstream. 

"This new application of LIF is an avenue of therapy that has not been explored in human patients with MS," says Deverman, who points out that LIF's benefits might also be good for spinal-cord injury patients since the demyelination of spared neurons may contribute to disability in that disorder.

To move the research closer to human clinical trials, the team will work to build better viral vectors for the delivery of LIF. "The way this gene therapy works is to use a virus that can deliver the genetic material—LIF—into cells," explains Patterson. "This kind of delivery has been used before in humans, but the worry is that you can't control the virus. You can't necessarily target the right place, and you can't control how much of the protein is being made."  

Which is why he and Deverman are developing viruses that can target LIF production to specific cell types and can turn it on and off externally, providing a means to regulate LIF levels. They also plan to test the therapy in additional MS mouse models.

"For MS, the current therapies all work by modulating or suppressing the immune system, because it's thought to be a disease in which inflammation leads to immune-associated loss of oligodendrocytes and damage to the neurons," says Deverman. "Those therapies can reduce the relapse rate in patients, but they haven't shown much of an effect on the long-term progression of the disease. What are needed are therapies that promote repair. We hope this may one day be such a therapy." 

The work done in this study, "Exogenous Leukemia Inhibitory Factor Stimulates Oligodendrocyte Progenitor Cell Proliferation and Enhances Hippocampal Remyelination," was funded by the California Institute for Regenerative Medicine, the National Institutes of Neurological Disorders and Stroke, and the McGrath Foundation.

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Two Caltech Researchers Receive Frontiers of Knowledge Award

For their work in information and communication technologies, and biomedicine, Carver Mead, Moore Professor Emeritus of Engineering and Applied Science, and Alexander Varshavsky, Smits Professor of Cell Biology, have been honored by the BBVA Foundation as recipients of 2011 Frontiers of Knowledge awards. The BBVA Foundation—a social responsibility arm of the multinational Spanish banking group Banco Bilbao Vizcaya Argentaria (BBVA)—presents the 400,000 euro (approximately $520,000) awards to recognize world-class research and "contributions of lasting impact for their originality, theoretical significance, and ability to push back the frontiers of the known world." For more information on the awards, and to read profiles on the winners, click here.

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Alexander Varshavsky Receives King Faisal International Prize for Science

Alexander Varshavsky, Caltech's Howard and Gwen Laurie Smits Professor of Cell Biology, has been awarded the 2012 King Faisal International Prize (KFIP) for Science. The winners of the prize, which also includes awards for medicine, Arabic language and literature, Islamic studies, and service to Islam, were announced in Riyadh, Saudi Arabia, on January 16.

Presented by the King Faisal Foundation, the prize seeks to honor "scholars and scientists who have made significant contributions and advances in areas that benefit developing and Islamic countries, and humanity at large." According to the organization, many winners of the KFIP have gone on to win Nobel prizes for their work.

Varshavsky was recognized for his groundbreaking work in cell biology, including advances that have "created a new realm of biology and have been essential for progress in research on human cancer, neurodegeneration, immune responses, and other fundamental biological processes."

His main recognized contribution was the fundamental discovery, in the 1980s, of biological regulation by intracellular protein degradation and its central importance in cellular physiology. This discovery by the Varshavsky laboratory involved the understanding, through genetic and biochemical insights, of the biological functions of the ubiquitin system, a major proteolytic circuit in living cells. Ubiquitin is a small protein that is present in cells either as a free protein or as a part of complexes with many other proteins. The association of ubiquitin with cellular proteins marks them for degradation or other metabolic fates. Through its ability to destroy specific proteins, the ubiquitin system plays a major role in cell growth and differentiation, DNA repair, regulation of gene expression, and many other biological processes.

"Alex has been a true pioneer in cell biology and this well-deserved award is further recognition of the significance of his work and its broad impact across the biological sciences," says Stephen Mayo, Bren Professor of Biology and Chemistry and chair of the Division of Biology.

Varshavsky is a member of the National Academy of Sciences, the American Academy of Arts and Sciences, the American Philosophical Society, and the Academia Europaea. He has received many international prizes in biology and medicine, including the 2011 Otto Warburg Prize (Germany); the 2008 Gotham Prize in Cancer Research; the 2006 Gagna Prize (Belgium); the 2006 Griffuel Prize (France); the 2005 Stein and Moore Award; the 2001 Horwitz Prize; the 2001 Merck Award; the 2001 Wolf Prize in Medicine (Israel); the 2000 Lasker Award in Basic Medical Research; and the 1999 Gairdner International Award (Canada).

Nominations for the KFIP are accepted from organizations and universities throughout the world, and winners are selected through peer review and a committee of experts in the given field. A total of 47 scholars from 11 different countries have won the prize for science, which was first awarded in 1984. The winners will receive their awards, which include a cash prize of 750,000 Saudi riyals ($200,000), in March during a special ceremony held in Riyadh under the auspices of the king of Saudi Arabia. 

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