A Detailed Look at HIV in Action

Researchers gain a better understanding of the virus through electron microscopy

The human intestinal tract, or gut, is best known for its role in digestion. But this collection of organs also plays a prominent role in the immune system. In fact, it is one of the first parts of the body that is attacked in the early stages of an HIV infection. Knowing how the virus infects cells and accumulates in this area is critical to developing new therapies for the over 33 million people worldwide living with HIV. Researchers at the California Institute of Technology (Caltech) are the first to have utilized high-resolution electron microscopy to look at HIV infection within the actual tissue of an infected organism, providing perhaps the most detailed characterization yet of HIV infection in the gut.

The team's findings are described in the January 30 issue of PLOS Pathogens.

"Looking at a real infection within real tissue is a big advance," says Mark Ladinsky, an electron microscope scientist at Caltech and lead author of the paper. "With something like HIV, it's usually very difficult and dangerous to do because the virus is an infectious agent. We used an animal model implanted with human tissue so we can study the actual virus under, essentially, its normal circumstances."

Ladinsky worked with Pamela Bjorkman, Max Delbrück Professor of Biology at Caltech, to take three-dimensional images of normal cells along with HIV-infected tissues from the gut of a mouse model engineered to have a human immune system. The team used a technique called electron tomography, in which a tissue sample is embedded in plastic and placed under a high-powered microscope. Then the sample is tilted incrementally through a course of 120 degrees, and pictures are taken of it at one-degree intervals. All of the images are then very carefully aligned with one another and, through a process called back projection, turned into a 3-D reconstruction that allows different places within the volume to be viewed one pixel at a time.

"Most prior electron microscopy studies of HIV have focused on the virus itself or on infection of laboratory-grown cell cultures," says Bjorkman, who is also an investigator with the Howard Hughes Medical Institute. "Ours is the first major electron microscopy study to look at HIV interacting with other cells in the actual gut tissue of an infected animal model."

By procuring such detailed images, Ladinsky and Bjorkman were able to confirm several observations of HIV made in prior, in vitro studies, including the structure and behavior of the virus as it buds off of infected cells and moves into the surrounding tissue and structural details of HIV budding from cells within an infected tissue. The team also described several novel observations, including the existence of "pools" of HIV in between cells, evidence that HIV can infect new cells both by direct contact or by free viruses in the same tissue, and that pools of HIV can be found deep in the gut.

"The study suggests that an infected cell releases newly formed viruses in a semisynchronous wave pattern," explains Ladinsky. "It doesn't look like one virus buds off and then another in a random way. Rather, it appears that groups of virus bud off from a given cell within a certain time frame and then, a little while later, another group does the same, and then another, and so on."

The team came to this conclusion by identifying single infected cells using electron microscopy. Then they looked for HIV particles at different distances from the original cell and saw that the groups of particles were more mature as their distance from the infected cell increased.

"This finding showed that indeed these cells were producing waves of virus rather than individual ones, which was a neat observation," says Ladinsky.

In addition to producing waves of virus, infected cells are also thought to spread HIV through direct contact with their neighbors. Bjorkman and Ladinsky were able to visualize this phenomenon, known as a virological synapse, using electron microscopy.

"We were able to see one cell producing a viral bud that is contacting the cell next to it, suggesting that it's about to infect directly," Ladinsky says. "The space between those two cells represents the virological synapse."

Finally, the team found pools of HIV accumulating between cells where there was no indication of a virological synapse. This suggested that a virological synapse, which may be protected from some of the body's immune defenses, is not the only way in which HIV can infect new cells. The finding of HIV transfer via free pools of free virus offers hope that treatment with protein-based drugs, such as antibodies, could be an effective means of augmenting or replacing current treatment regimens that use small-molecule antiretroviral drugs.

"We saw these pools of virus in places where we had not initially expected to see them, down deep in the intestine," he explains. "Most of the immune cells in the gut are found higher up, so finding large amounts of the virus in the crypt regions was surprising."

The team will continue their efforts to look at HIV and related viruses under natural conditions using additional animal models, and potentially people.

"The end goal is to look at a native infection in human tissue to get a real picture of how it's working inside the body, and hopefully make a positive difference in fighting this epidemic," says Bjorkman.

Additional authors on the PLOS Pathogens paper, "Electron Tomography of HIV-1 Infection in Gut-Associated Lymphoid Tissue," are Collin Kieffer, a postdoctoral scholar in biology at Caltech; Gregory Olson and Douglas S. Kwon from the Ragon Institute of Massachusetts General Hospital (MGH), MIT, and Harvard; and Maud Deruaz, Vladimir Vrbanac, and Andrew M. Tager from MGH and Harvard Medical School. The work was supported by the Center for the Structural Biology of Cellular Host Elements in Egress, Trafficking and Assembly of HIV (CHEETAH).

 

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Worry on the Brain

Caltech researchers pinpoint neural circuitry that promotes stress-induced anxiety

According to the National Institute of Mental Health, over 18 percent of American adults suffer from anxiety disorders, characterized as excessive worry or tension that often leads to other physical symptoms. Previous studies of anxiety in the brain have focused on the amygdala, an area known to play a role in fear. But a team of researchers led by biologists at the California Institute of Technology (Caltech) had a hunch that understanding a different brain area, the lateral septum (LS), could provide more clues into how the brain processes anxiety. Their instincts paid off—using mouse models, the team has found a neural circuit that connects the LS with other brain structures in a manner that directly influences anxiety.

"Our study has identified a new neural circuit that plays a causal role in promoting anxiety states," says David Anderson, the Seymour Benzer Professor of Biology at Caltech, and corresponding author of the study. "Part of the reason we lack more effective and specific drugs for anxiety is that we don't know enough about how the brain processes anxiety. This study opens up a new line of investigation into the brain circuitry that controls anxiety."

The team's findings are described in the January 30 version of the journal Cell.

Led by Todd Anthony, a senior research fellow at Caltech, the researchers decided to investigate the so-called septohippocampal axis because previous studies had implicated this circuit in anxiety, and had also shown that neurons in a structure located within this axis—the LS—lit up, or were activated, when anxious behavior was induced by stress in mouse models. But does the fact that the LS is active in response to stressors mean that this structure promotes anxiety, or does it mean that this structure acts to limit anxiety responses following stress? The prevailing view in the field was that the nerve pathways that connect the LS with different brain regions function as a brake on anxiety, to dampen a response to stressors. But the team's experiments showed that the exact opposite was true in their system.

In the new study, the team used optogenetics—a technique that uses light to control neural activity—to artificially activate a set of specific, genetically identified neurons in the LS of mice. During this activation, the mice became more anxious. Moreover, the researchers found that even a brief, transient activation of those neurons could produce a state of anxiety lasting for at least half an hour. This indicates that not only are these cells involved in the initial activation of an anxious state, but also that an anxious state persists even after the neurons are no longer being activated.

"The counterintuitive feature of these neurons is that even though activating them causes more anxiety, the neurons are actually inhibitory neurons, meaning that we would expect them to shut off other neurons in the brain," says Anderson, who is also an investigator with the Howard Hughes Medical Institute (HHMI).

So, if these neurons are shutting off other neurons in the brain, then how can they increase anxiety? The team hypothesized that the process might involve a double-inhibitory mechanism: two negatives make a positive. When they took a closer look at exactly where the LS neurons were making connections in the brain, they saw that they were inhibiting other neurons in a nearby area called the hypothalamus. Importantly, most of those hypothalamic neurons were, themselves, inhibitory neurons. Moreover, those hypothalamic inhibitory neurons, in turn, connected with a third brain structure called the paraventricular nucleus, or PVN. The PVN is well known to control the release of hormones like cortisol in response to stress and has been implicated in anxiety.

This anatomical circuit seemed to provide a potential double-inhibitory pathway through which activation of the inhibitory LS neurons could lead to an increase in stress and anxiety. The team reasoned that if this hypothesis were true, then artificial activation of LS neurons would be expected to cause an increase in stress hormone levels, as if the animal were stressed. Indeed, optogenetic activation of the LS neurons increased the level of circulating stress hormones, consistent with the idea that the PVN was being activated. Moreover, inhibition of LS projections to the hypothalamus actually reduced the rise in cortisol when the animals were exposed to stress. Together these results strongly supported the double-negative hypothesis.

"The most surprising part of these findings is that the outputs from the LS, which were believed primarily to act as a brake on anxiety, actually increase anxiety," says Anderson.

Knowing the sign—positive or negative—of the effect of these cells on anxiety, he says, is a critical first step to understanding what kind of drug one might want to develop to manipulate these cells or their molecular constituents. If the cells had been found to inhibit anxiety, as originally thought, then one would want to find drugs that activate these LS neurons, to reduce anxiety. However, since the group found that these neurons instead promote anxiety, then to reduce anxiety a drug would have to inhibit these neurons.

"We are still probably a decade away from translating this very basic research into any kind of therapy for humans, but we hope that the information that this type of study yields about the brain will put the field and medicine in a much better position to develop new, rational therapies for psychiatric disorders," says Anderson. "There have been very few new psychiatric drugs developed in the last 40 to 50 years, and that's because we know so little about the brain circuitry that controls the emotions that go wrong in a psychiatric disorder like depression or anxiety."

The team will continue to map out this area of the brain in greater detail to understand more about its role in controlling stress-induced anxiety.

"There is no shortage of new questions that have been raised by these findings," Anderson says. "It may seem like all that we've done here is dissect a tiny little piece of brain circuitry, but it's a foothold onto a very big mountain. You have to start climbing someplace."

Additional authors on the Cell paper, "Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit," are Walter Lerchner from the National Institutes of Health (NIH), Nick Dee and Amy Bernard from the Allen Institute for Brain Science, and Nathaniel Heintz from The Rockefeller University and HHMI. The work was supported by NIH, HHMI, and the Beckman Institute at Caltech.

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Monday, May 5, 2014
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Fighting Flies

Caltech biologists identify sex-specific brain cells in male flies that promote aggression

When one encounters a group of fruit flies invading their kitchen, it probably appears as if the whole group is vying for a sweet treat. But a closer look would likely reveal the male flies in the group are putting up more of a fight, particularly if ripe fruit or female flies are present. According to the latest studies from the fly laboratory of California Institute of Technology (Caltech) biologist David Anderson, male Drosophilae, commonly known as fruit flies, fight more than their female counterparts because they have special cells in their brains that promote fighting. These cells appear to be absent in the brains of female fruit flies.  

"The sex-specific cells that we identified exert their effects on fighting by releasing a particular type of neuropeptide, or hormone, that has also been implicated in aggression in mammals including mouse and rat," says Anderson, the Seymour Benzer Professor of Biology at Caltech, and corresponding author of the study. "In addition, there are some recent papers implicating increased levels of this hormone in people with personality disorders that lead to higher levels of aggression."

The team's findings are outlined in the January 16 version of the journal Cell.

At first glance, a fruit fly may seem nothing like a human being. But look much closer, at a genetic level, and you will find that many of the genes seen in these flies are also present—and play similar roles—in humans. However, while such conservation holds for genes involved in basic cellular functions and in development, whether it was also true for genes controlling complex social behaviors like aggression was far from clear.

"Our studies are the first, to our knowledge, to identify a gene that plays a conserved role in aggression all the way from flies to humans," explains Anderson, who is also a Howard Hughes Medical Institute investigator. If that is true for one such gene, it is also is likely true for others, Anderson says. "Our study validates using fruit flies as a model to discover new genes that may also control aggression in humans."

The less-complex nervous system of the fruit fly makes them easier to study than people or even mice, another genetic model organism. For this particular study, the research team created a small library consisting of different fly lines; in each line, a different set of specific neurons was genetically labeled and could be artificially activated, with each neuron type secreting a different neuropeptide. Forty such lines were tested for their ability to increase aggression when their labeled neurons were activated. The one that produced the most dramatic increase in aggression had neurons expressing a particular neuropeptide called tachykinin, or Tk.

Next, Anderson and his colleagues used a set of genetic tools to identify exactly which neurons were responsible for the effect on aggression and to see if the gene that encodes for Tk also controls aggressive behavior by acting in that cell.

"We had to winnow away the different cells to find exactly which ones were involved in aggression—that's how we discovered that within this line, there was a male-specific set of neurons that was responsible for increased aggressive behavior," explains Kenta Asahina, a postdoctoral scholar in Anderson's lab and lead author of the study. Male-specific neurons controlling courtship behavior had previously been identified in flies, but this was the first time a male-specific neuron was found that specifically controls aggression. Having identified that neuron, the team was then able to modify its gene expression. Says Asahina, "We found that if you overproduce the gene in that cell and then stimulate the cell, you get an even stronger effect to promote aggression than if you stimulate the cell without overproducing the gene."

In fact, combining cell activation and the overproduction of the neuropeptide, which is released when the cell is activated, caused the flies to attack targets they normally would not. For example, when the researchers eliminated cues that normally promote aggression in a target fly — such as pheromones — the flies containing the hyperactivated "aggression" neurons attacked those targets despite the absence of the cues.

Moreover, this combined activation of the cell and the gene produced such a strong effect that the researchers were even able to get a fly to attack an inanimate object—a fly-sized magnet—when it was moved around in an arena.

Such behavior had never been observed previously. "A normal fly will chase the magnet, but will never attack the magnet," Asahina explains. "By over-activating these neurons, we are able to get the fly to attack an object that displays none of the normal signals that are required to elicit aggression from another fly."

"These results suggest that what these neurons are doing is promoting a state of aggressive arousal in the fly," Anderson says. "This elevated level of aggressiveness drives the fly to attack targets it would normally ignore. I wouldn't anthropomorphize the fly and say that it has increased 'anger,' but activating these neurons greatly lowers its threshold for attack."

The finding that these neurons are present in the brains of male but not female flies indicates that this sex difference in aggressive behavior is genetically based. At the same time, Asahina stresses, finding a gene that influences aggression does not mean that aggression is controlled only by genes and always genetically programmed.

"This is a very important distinction, because when people hear about a gene implicated in behavior, they automatically think it means that the behavior is genetically determined. But that is not necessarily the case," he says. "The key point here is that we can say something about how the gene acts to influence this behavior—that is, is by functioning as a chemical messenger in cells that control this behavior in the brain. We've been able to study the problem of aggressive behavior at two levels, the cell level and the gene level, and to link those studies together by genetic experiments."

This research, Anderson says, has given his team a beachhead into the circuitry in the fly brain that controls aggression, a behavior that they will continue to try to decode.

"We have to use this point of entry to discover the larger circuit in which those cells function," Anderson says. "If aggression is like a car, and if more aggression is like a car going faster, we want to know if what we're doing when we trigger these cells is stepping on the gas or taking the foot off the brake. And we want to know where and how that's happening in the brain. That's going to take a lot of work."

Additional Caltech authors on the Cell paper, "Male-specific Tachykinin-expressing neurons control sex differences in levels of aggressiveness in Drosophila," are Kiichi Watanabe, Brian J. Duistermars, Eric Hoopfer, Carlos Roberto González, Eyrún Arna Eyjólfsdóttir, and Pietro Perona. Their work was supported by the National Institutes of Health, a grant from the Gordon and Betty Moore Foundation, the Japan Society for the Promotion of Science, and the Howard Hughes Medical Institute.

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Bacterial "Syringe" Necessary for Marine Animal Development

If you've ever slipped on a slimy wet rock at the beach, you have bacteria to thank. Those bacteria, nestled in a supportive extracellular matrix, form bacterial biofilms—often slimy substances that cling to wet surfaces. For some marine organisms—like corals, sea urchins, and tubeworms—these biofilms serve a vital purpose, flagging suitable homes for such organisms and actually aiding the transformation of larvae to adults.

A new study at the California Institute of Technology (Caltech) is the first to describe a mechanism for this phenomenon, providing one explanation for the relationship between bacterial biofilms and the metamorphosis of marine invertebrates. The results were published online in the January 9 issue of Science Express.

The study focused on a marine invertebrate that has become a nuisance to the shipping industry since its arrival in U.S. waters during the last half century: the tubeworm Hydroides elegans. The larvae of the invasive pest swim free in the ocean until they come into contact with a biofilm-covered surface, such as a rock or a buoy—or the hull of a ship. After the tubeworm larvae come in contact with the biofilm, they develop into adult worms that anchor to the surface, creating hard, mineralized "tubes" around their bodies. These tubes, which often cover the bottoms of ships, create extra drag in the water, dramatically increasing the ship's fuel consumption.

The tubeworms' unwanted and destructive presence on ships, called biofouling, is a "really bad problem," says Dianne Newman, a professor of biology and geobiology and Howard Hughes Medical Institute (HHMI) investigator at Caltech. "For example, biofouling costs the U.S. Navy millions of dollars every year in excess fuel costs," says Newman, who is also a coauthor of the study. And although researchers have known for decades that biofilms are necessary for tubeworm development, says Nicholas Shikuma, one of the two first authors on the study and a postdoctoral scholar in Newman's laboratory, "there was no mechanistic explanation for how bacteria can actually induce that process to happen. We wanted to provide that explanation."

Shikuma began by investigating Pseudoalteromonas luteoviolacea, a bacterial species known to induce metamorphosis in the tubeworm and other marine invertebrates. In earlier work, Michael G. Hadfield of the University of Hawai'i at Mānoa, a coauthor of the Science Express paper, had identified a group of P. luteoviolacea genes that were necessary for tubeworm metamorphosis. Near those genes, Shikuma found a set of genes that produced a structure similar to the tail of bacteriophage viruses.

The tails of these phage viruses contain three main components: a projectile tube, a contractile sheath that deploys the tube, and an anchoring baseplate. Together, the phage uses these tail components as a syringe, injecting their genetic material into host bacteria cells, infecting—and ultimately killing—them. To determine if the phage tail-like structures in P. luteoviolacea played a role in tubeworm metamorphosis, the researchers systematically deleted the genes encoding each of these three components.

Electron microscope images of the bacteria confirmed that syringe-like structures were present in "normal" P. luteoviolacea cells but were absent in cells in which the genes encoding the three structural components had been deleted; these genes are known as metamorphosis-associated contractile structure (mac) genes. The researchers also discovered that the bacterial cells lacking mac genes were unable to induce metamorphosis in tubeworm larvae. Previously, the syringe-like structures had been found in other species of bacteria, but in these species, the tails were deployed to kill other bacteria or insects. The new study provides the first evidence of such structures benefitting another organism, Shikuma says.

In order to view the three-dimensional arrangement of these unique structures within intact bacteria, the researchers collaborated with the laboratory of Grant Jensen, professor of biology and HHMI investigator at Caltech. Utilizing a technique called electron cryotomography, the researchers flash-froze the bacterial cells at very low temperatures. This allowed them to view the cells and their internal structures in their natural, "near-native" states.

Using this visualization technique, Martin Pilhofer, a postdoctoral scholar in Jensen's lab and the paper's other first author, discovered something unique about the phage tail-like structures within P. luteoviolacea; instead of existing as individual appendages, the structures were linked together to create a spiny array. "In these arrays, about 100 tails are stuck together in a hexagonal lattice to form a complex with a porcupine-like appearance," Shikuma says. "They're all facing outward, poised to fire," he adds. "We believe this is the first observation of arrays of phage tail-like structures."

Initially, the array is compacted within each bacterium; however, the cells eventually burst—killing the microbes—and the array unfolds. The researchers hypothesize that, at this point, the individual spines of the array fire outward into the tubeworm larva. Following this assault, the larvae begin their developmental transition to adulthood.

"It was a tremendous surprise that the agent that drives metamorphosis is such an elaborate, well-organized injection machine," says coauthor Jensen. "Who would have guessed that the signal is delivered by an apparatus that is almost as large as the bacterial cell itself? It is simply a marvelous structure, synthesized in a 'loaded' but tightly collapsed state within the cell, which then expands like an umbrella, opening up into a much larger web of syringes that are ready to inject," he says.

Although the study confirms that the phage tail-like structures can cause tubeworm metamorphosis, the nature of the interaction between the tail and the tubeworm is still unknown, Shikuma says. "Our next step is to determine whether metamorphosis is caused by an injection into the tubeworm larva tissue, and, then, if the mechanical action is the trigger, or if the bacterium is injecting a chemical morphogen," he says. He and his colleagues would also like to determine if mac genes and the tail-like structures they encode might influence other marine invertebrates, such as corals and sea urchins, that also rely on P. luteoviolacea biofilms for metamorphosis.

Understanding this process might one day help reduce the financial losses from P. luteoviolacea biofilm fouling on ship hulls, for example. While applications are a long way off, Newman says, it is also interesting to speculate on the possibility of leveraging metamorphosis induction in beneficial marine invertebrates to improve yields in aquaculture and promote coral reef growth.

The study, the researchers emphasize, is an example of the collaborative research that is nurtured at Caltech. For his part, Shikuma was inspired to utilize electron cryotomography after hearing a talk by Martin Pilhofer at the Center for Environmental Microbiology Interactions (CEMI) at Caltech. "Martin gave a presentation on another type of phage tail-like structures in the monthly CEMI seminar. I saw his talk and I thought that the mac genes I was working with might somehow be related," Shikuma says. Their subsequent collaboration, Newman says, made the current study possible.

The paper is titled "Marine tubeworm metamorphosis induced by arrays of bacterial phage tail-like structures." Gregor L. Weiss, a Summer Undergraduate Research Fellowship student in Jensen's laboratory at Caltech, was an additional coauthor on the study. The published work was funded by a Caltech Division of Biology Postdoctoral Fellowship (to N. Shikuma), the Caltech CEMI, the Howard Hughes Medical Institute, the Office of Naval Research, the National Institutes of Health, and the Gordon and Betty Moore Foundation.

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Caltech Cell Biologist Wins $3 Million Breakthrough Prize in Life Sciences

Alexander Varshavsky, Caltech's Howard and Gwen Laurie Smits Professor of Cell Biology, has been awarded one of six 2014 Breakthrough Prizes in Life Sciences. Varshavsky was honored for "his discovery of the critical molecular determinants and biological functions of intracellular protein degradation," according to the award citation.

Each of the laureates will receive $3 million, making the award, announced at a ceremony at NASA's Ames Research Center on December 12, one of the largest academic prizes in the world.

At the same ceremony, Caltech's John Schwarz, the Harold Brown Professor of Theoretical Physics, and Michael B. Green of the University of Cambridge were named winners of the 2014 Fundamental Physics Prize in recognition of the new perspectives they have brought to quantum gravity and the unification of the fundamental physical forces of the universe. They will share a $3 million award.

Caltech's Alexei Kitaev, Ronald and Maxine Linde Professor of Theoretical Physics and Mathematics, is a previous winner of the Fundamental Physics Prize.

The Breakthrough Prize in Life Sciences was instituted to recognize "excellence in research aimed at curing intractable diseases and extending human life," according to the Breakthrough Prize in Life Sciences Foundation website. Founding sponsors of the prize include Sergey Brin and Anne Wojcicki, Mark Zuckerberg and Priscilla Chan, Jack Ma and Cathy Zhang, and Yuri Milner.

The inaugural class of 11 prize winners, announced in February, served on the selection committee for the 2014 awards; Varshavsky and the other laureates will join the selection committee for future awardees.

Varshavsky was noted for the fundamental discovery, in the 1980s, of biological regulation by intracellular protein degradation and its central importance in cellular physiology. "Studies by my laboratory, at first at the Massachusetts Institute of Technology and later at Caltech, focused on the understanding of how and why cells destroy their own proteins to withstand stress, to grow and divide, to differentiate into new kinds of cells, and to do countless other things that make living organisms so astonishing and fascinating," Varshavsky says.

His work focuses on the design and 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 tight (covalent) 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.

"The field of ubiquitin has been expanding at an amazing pace and is now one of the largest arenas in biomedical science," Varshavsky says. "Both earlier and recent discoveries illuminate the ubiquitin system and protein degradation from many different angles and continue to foster our ability to tackle human diseases, from cancer, infections and cardiovascular illnesses to neurodegenerative syndromes and aging itself. I feel privileged having been able to contribute to the birth of this field and to partake in its later development.

"The Breakthrough Prize will support, in a major way, our studies at Caltech," Varshavsky adds. "I am most grateful to the Breakthrough Foundation, to its founders, and to its committee for the honor of this award."

"The Breakthrough Prize in Life Sciences recognizes Alex's truly pioneering discovery of ubiquitin-mediated protein degradation and its central role in both cellular function and dysfunction. His work has opened up completely new approaches to understanding and treating human disease," says Stephen Mayo, Bren Professor of Biology and Chemistry and the William K. Bowes Jr. Leadership Chair of the Division of Biology and Biological Engineering.

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.

A member of the National Academy of Sciences, the American Academy of Arts and Sciences, the American Philosophical Society, and the Academia Europaea, Varshavsky has received many international prizes in biology and medicine, including the 2012 King Faisal International Prize for Science (Saudi Arabia), 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).

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Probiotic Therapy Alleviates Autism-like Behaviors in Mice

Autism spectrum disorder (ASD) is diagnosed when individuals exhibit characteristic behaviors that include repetitive actions, decreased social interactions, and impaired communication. Curiously, many individuals with ASD also suffer from gastrointestinal (GI) issues, such as abdominal cramps and constipation.

Using the co-occurrence of brain and gut problems in ASD as their guide, researchers at the California Institute Technology (Caltech) are investigating a potentially transformative new therapy for autism and other neurodevelopmental disorders.

The gut microbiota—the community of bacteria that populate the human GI tract—previously has been shown to influence social and emotional behavior, but the Caltech research, published online in the December 5 issue of the journal Cell, is the first to demonstrate that changes in these gut bacteria can influence autism-like behaviors in a mouse model.

"Traditional research has studied autism as a genetic disorder and a disorder of the brain, but our work shows that gut bacteria may contribute to ASD-like symptoms in ways that were previously unappreciated," says Professor of Biology Sarkis K. Mazmanian. "Gut physiology appears to have effects on what are currently presumed to be brain functions."

To study this gut–microbiota–brain interaction, the researchers used a mouse model of autism previously developed at Caltech in the laboratory of Paul H. Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences. In humans, having a severe viral infection raises the risk that a pregnant woman will give birth to a child with autism. Patterson and his lab reproduced the effect in mice using a viral mimic that triggers an infection-like immune response in the mother and produces the core behavioral symptoms associated with autism in the offspring.

In the new Cell study, Mazmanian, Patterson, and their colleagues found that the "autistic" offspring of immune-activated pregnant mice also exhibited GI abnormalities. In particular, the GI tracts of autistic-like mice were "leaky," which means that they allow material to pass through the intestinal wall and into the bloodstream. This characteristic, known as intestinal permeability, has been reported in some autistic individuals. "To our knowledge, this is the first report of an animal model for autism with comorbid GI dysfunction," says Elaine Hsiao, a senior research fellow at Caltech and the first author on the study.

To see whether these GI symptoms actually influenced the autism-like behaviors, the researchers treated the mice with Bacteroides fragilis, a bacterium that has been used as an experimental probiotic therapy in animal models of GI disorders.

The result? The leaky gut was corrected.

In addition, observations of the treated mice showed that their behavior had changed. In particular, they were more likely to communicate with other mice, had reduced anxiety, and were less likely to engage in a repetitive digging behavior.

"The B. fragilis treatment alleviates GI problems in the mouse model and also improves some of the main behavioral symptoms," Hsiao says. "This suggests that GI problems could contribute to particular symptoms in neurodevelopmental disorders."

With the help of clinical collaborators, the researchers are now planning a trial to test the probiotic treatment on the behavioral symptoms of human autism. The trial should begin within the next year or two, says Patterson.

"This probiotic treatment is postnatal, which means that the mother has already experienced the immune challenge, and, as a result, the growing fetuses have already started down a different developmental path," Patterson says. "In this study, we can provide a treatment after the offspring have been born that can help improve certain behaviors. I think that's a powerful part of the story."

The researchers stress that much work is still needed to develop an effective and reliable probiotic therapy for human autism—in part because there are both genetic and environmental contributions to the disorder, and because the immune-challenged mother in the mouse model reproduces only the environmental component.

"Autism is such a heterogeneous disorder that the ratio between genetic and environmental contributions could be different in each individual," Mazmanian says. "Even if B. fragilis ameliorates some of the symptoms associated with autism, I would be surprised if it's a universal therapy—it probably won't work for every single case."

The Caltech team proposes that particular beneficial bugs are intimately involved in regulating the release of metabolic products (or metabolites) from the gut into the bloodstream. Indeed, the researchers found that in the leaky intestinal wall of the autistic-like mice, certain metabolites that were modulated by microbes could both easily enter the circulation and affect particular behaviors.

"I think our results may someday transform the way people view possible causes and potential treatments for autism," Mazmanian says.

Along with Patterson, Hsiao, and Mazmanian, additional Caltech coauthors on the paper, "Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders," are Sara McBride, Sophia Hsien, Gil Sharon, Julian A. Codelli, Janet Chow, and Sarah E. Reisman. The work was supported by a Caltech Innovation Initiative grant, an Autism Speaks Weatherstone Fellowship, a National Institutes of Health/National Research Service Award Ruth L. Kirschstein Predoctoral Fellowship, a Human Frontiers Science Program Fellowship, a Department Of Defense Graduate Fellowship, a National Science Foundation Graduate Research Fellowship, an Autism Speaks Trailblazer Award, a Caltech Grubstake award, a Congressionally Directed Medical Research Award, a Weston Havens Foundation Award, several Callie McGrath Charitable Foundation awards, and the National Institute of Mental Health.

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