Wordy Worms

Lurking in the crevices of our planet are millions and millions of microscopic worms. They live in soil, plants, water, ice, wildlife, and sometimes even humans. In fact, nematodes—also known as roundworms—are among the most abundant and diverse animals on Earth, where they play a variety of roles.

For the past 25 years, Paul Sternberg, the Thomas Hunt Morgan Professor of Biology at Caltech and a Howard Hughes Medical Institute investigator, has been studying the development and behavior of these creepy-crawly creatures and has recently uncovered important clues about how the worms communicate.

Read about his findings in the Fall 2012 issue of E&S magazine.

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Traveling with Purpose

Biologist spends summer vacation volunteering in India

Pamela Bjorkman has been studying HIV at Caltech since 2005. In the lab, she has made significant gains in the fight against the virus, developing antibodies that neutralize most strains. But years spent at the bench were beginning to make her feel disconnected from the possible impact of her work. So this summer she visited India, spending time with HIV-positive women and others who are at risk.

"What I wanted to do was see the real side of HIV, where it affects people," says Bjorkman, the Max Delbrück Professor of Biology and an investigator with the Howard Hughes Medical Institute. "We work in the lab where we have no contact with HIV-infected people—the human impact of the disease is very removed from what we think about in our work."

This was not her first trip to the nation of over 1.2 billion people, where nearly 30 percent of the population lives in poverty. She first visited in 1985 and returned with her teenage daughter in 2008 to work at an orphanage in the Jaipur area called Udayan. The home for children is part of an umbrella organization called Vatsalya that also runs an HIV-education program for female sex workers, among other projects aimed at empowering women and teaching street children vocational skills.

"The orphanage is really incredible," says Bjorkman, whose daughter accompanied her on her most recent trip as well. "There are an estimated 18 million children living on the street in India—a lot who are not actually orphans, but on the street anyway. The organization takes in as many children as it can—around 60—and those kids are never adopted. When they come to the orphanage, the group there becomes their family."

The mission of the organization—founded in 1995 by Jaimala and Hitesh Gupta, both of whom have backgrounds in public health—is to "provide a caring environment where our disadvantaged and vulnerable people can develop their capabilities with dignity." The orphanage is a nearly self-sufficient compound that includes a school, a farm, a garden, and dormitories. They even have a psychologist who visits with the children, many of whom suffered abuse at very young ages.

"It's really an amazing place," says Bjorkman. "Here these kids are, all living with the most horrible back stories, and they are full of joy and respectful and helpful. It makes you realize how incredibly privileged we are here in Pasadena and that we take a lot for granted."

Bjorkman and her daughter stayed at Udayan for two weeks each time they visited, helping to teach the children English and math, participating in art and dance projects, and helping with gardening and cooking. This summer, Bjorkman also traveled to Ajmer, where the group's HIV-education program is located. There, she met with women struggling with the stigma of HIV, particularly because they rely on sex work to support their children and send them to private school; public schools in many impoverished areas of India are notoriously bad.

"The organization identifies women in the community who are sex workers and are interested in learning some other trade, or who need help because of HIV infection," she explains. "The terrible thing is that when they find out they are HIV infected, many of the women start working more because their futures are more uncertain.  Plus, they hesitate to take medication because if anyone finds out that they are positive, they will lose customers." 

The organization provides counseling, runs a female condom education program, offers training classes for those wanting to become proficient at another job, and works to get HIV-positive women on antiretroviral medications. While visiting with the women, Bjorkman talked with them about how the virus works and why it's so tough to treat once it's in the body.

"This is the reason that I'm doing the HIV research," she says. "It's not to get our own papers out first, it's to actually do something that might make a difference. Meeting the women put a lot of the competition and the unpleasantness associated with the rat race of science into perspective."

Bjorkman plans to return to India, but in the meantime she's doing all she can to raise awareness for Vatsalya and their various projects. Like any nonprofit, the organization could use monetary donations, but she hopes that her story inspires others at Caltech to donate their time. Anyone, she says, can volunteer through Vatsalya and receive room, board, and meals at the orphanage for a nominal daily donation.

"Caltech undergrad and grad students don't necessarily have that much money, but they may have time and this would be an amazing way to get to know another culture," she says. "These people are really doing a great job—both with the orphanage and with the HIV program that I had direct experience with. Once you see the way it works, it's really inspiring."

For more information on Vatsalya and the work they do, visit their website. Or contact Pamela Bjorkman to find out how you can become directly involved with this organization.  

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Caltech Again Named World's Top University in <i>Times Higher Education</i> Global Ranking

PASADENA, Calif.—The California Institute of Technology (Caltech) has been rated the world's number one university in the 2012–2013 Times Higher Education global ranking of the top 200 universities.

Oxford University, Stanford University, Harvard University, and MIT round out the top five.

"We are pleased to be among the best, and we celebrate the achievements of all our peer institutions," says Caltech president Jean-Lou Chameau. "Excellence is achieved over many years and is the result of our focus on extraordinary people. I am proud of our talented faculty, who educate outstanding young people while exploring transformative ideas in an environment that encourages collaboration rather than competition."

Times Higher Education compiled the listing using the same methodology as in last year's survey. Thirteen performance indicators representing research (worth 30 percent of a school's overall ranking score), teaching (30 percent), citations (30 percent), international outlook (which includes the total numbers of international students and faculty and the ratio of scholarly papers with international collaborators, 7.5 percent), and industry income (a measure of innovation, 2.5 percent) make up the data. Included among the measures are a reputation survey of 17,500 academics; institutional, industry, and faculty research income; and an analysis of 50 million scholarly papers to determine the average number of citations per scholarly paper, a measure of research impact.

In addition to placing first overall in this year's survey, Caltech came out on top in the teaching indicator as well as in subject-specific rankings for engineering and technology and for the physical sciences.

"Caltech held on to the world's number one spot with a strong performance across all of our key performance indicators," says Phil Baty, editor of the Times Higher Education World University Rankings. "In a very competitive year, when Caltech's key rivals for the top position reported increased research income, Caltech actually managed to widen the gap with the two universities in second place this year—Stanford University and the University of Oxford. This is an extraordinary performance."

Data for the Times Higher Education's World University Rankings were provided by Thomson Reuters from its Global Institutional Profiles Project, an ongoing, multistage process to collect and validate factual data about academic institutional performance across a variety of aspects and multiple disciplines.

The Times Higher Education site has the full list of the world's top 400 schools and all of the performance indicators.

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Caltech Biologist Named MacArthur Fellow

PASADENA, Calif.—Sarkis Mazmanian, a microbiology expert at the California Institute of Technology (Caltech) whose studies of human gut bacteria have revealed new insights into how these microbes can be beneficial, was named a MacArthur Fellow and awarded a five-year, $500,000 "no strings attached" grant. Each year, the John D. and Catherine T. MacArthur Foundation awards the unrestricted fellowships—also known as "genius" grants—to individuals who have shown "extraordinary originality and dedication in their creative pursuits and a marked capacity for self-direction," according to the foundation's website.

"I was in a state of shock when I heard the news," says Mazmanian, a professor of biology at Caltech, who was tricked into taking the award announcement call; he thought he was simply being added to a prescheduled conference call. "It's not the kind of thing you ever expect—I do what I do because I love science and it makes me happy, so this is terrific and a nice reward. At the same time, I never think of awards as goals of mine because they seem so unattainable. My goals are to make discoveries, so I was just in absolute disbelief."

Long before he was named a 2012 MacArthur Fellow, Mazmanian was showing the attributes that the foundation seeks to reward, particularly a capacity for self-direction. As a graduate student in the in the early 2000s, he decided to stray from the normal path of study and try something new. 

"I had been studying microbial pathogenesis—or bacteria that make us sick—which is what 99.9 percent of the field of microbiology does to this day," says Mazmanian. "Toward the end of my PhD, I decided that I wanted to study organisms that didn't necessarily cause disease, but were associated with our bodies. Ten years ago, this was completely on the fringe of science—we knew that the organisms existed in our intestines and all over our bodies, but had no idea what they were doing."  

Today, Mazmanian's work examines some of the trillions of bacteria living in our bodies that make up complex communities of microbes and regulate processes like digestion and immunity. His main focus is to understand how "good" bacteria promote human health—work that has transformed a quickly evolving field of research that is investigating the connection between gut bacteria and their relationship to both disease and health.

His research helped lay the groundwork for the Human Microbiome Project (HMP), an initiative of the National Institutes of Health that aims to characterize, for the first time, "the microbial communities found at several different sites on the human body, including nasal passages, oral cavities, skin, gastrointestinal tract, and urogenital tract, and to analyze the role of these microbes in human health and disease," according to the HMP website.

 

His laboratory was the first to demonstrate that specific gut bacteria direct the development of the mammalian immune system and provide protection from intestinal diseases. This means, he says, that fundamental aspects of health are absolutely dependent on microbial interaction within our bodies. In addition, he says that many disorders whose incidences are increasing in Western countries—such as inflammatory bowel disease, multiple sclerosis, and asthma—involve a common immunologic defect believed to be caused by the absence of intestinal bacteria. An understanding of the beneficial immune responses promoted by gut bacteria may lead to the development of natural therapeutics for immunologic and perhaps neurologic diseases, says Mazmanian.

"This award is extremely well-deserved—Sarkis has revolutionized the way we think about the interactions between microorganisms and people," says Stephen L. Mayo, William K. Bowes Jr. Foundation Chair of Caltech's Division of Biology, and Bren Professor of Biology and Chemistry. "His research has had an important impact in making the connection between personal hygiene and the immune system, and even neurological diseases like autism."

When the award announcement went public, Mazmanian was in Armenia, his native homeland, teaching a one-week course on host-microbial interaction to PhD students at a molecular biology institute. He travels to the country once a year to volunteer his services. The timing, he says, couldn't be better, as he hopes to use some of the prize money to develop an international educational outreach program.

"I think that when you have a windfall like this, the least you can do is help people who are in need," says Mazmanian, who credits the members of his lab for his research success. "In many countries, they are in need of education and resources, like lab equipment, text books, you name it. It would be a terrific if I could use the money to help advance science in countries where there is hardship."

Mazmanian received his bachelor's degree in 1995 and his PhD in microbiology in 2002, both from UCLA. Following a postdoctoral fellowship at Harvard, he joined the Caltech faculty as an assistant professor in 2006. In 2012, he was promoted to professor of biology. In 2011, Mazmanian was the recipient of a Burroughs Welcome Fund award for research in the pathogenesis of infectious disease, and in 2008 he was awarded a Searle Scholarship and was named one of Discover magazine's "20 Best Brains Under 40," which highlighted young innovators in science.

This year's crop of 23 Fellows includes stringed-instrument bow maker Benoît Rolland and mathematician Maria Chudnovsky; Mazmanian joins the ranks of Caltech's previous MacArthur Fellows, including 2010 awardee John Dabiri.

For more information on the 2012 MacArthur Fellows, visit the foundation website at www.macfound.org.

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Biologist Wins "Genius" Grant
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Ready for Your Close-Up?

Caltech study shows that the distance at which facial photos are taken influences perception

PASADENA, Calif.—As the saying goes, "A picture is worth a thousand words." For people in certain professions—acting, modeling, and even politics—this phrase rings particularly true. Previous studies have examined how our social judgments of pictures of people are influenced by factors such as whether the person is smiling or frowning, but until now one factor has never been investigated: the distance between the photographer and the subject. According to a new study by researchers at the California Institute of Technology (Caltech), this turns out to make a difference—close-up photo subjects, the study found, are judged to look less trustworthy, less competent, and less attractive.

The new finding is described in this week's issue of the open-access journal PLoS One.

Pietro Perona, the Allen E. Puckett Professor of Electrical Engineering at Caltech, came up with the initial idea for the study. Perona, an art history enthusiast, suspected that Renaissance portrait paintings often featured subtle geometric warping of faces to make the viewer feel closer or more distant to a subject. Perona wondered if the same sort of warping might affect photographic portraits—with a similar effect on their viewers—so he collaborated with Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology, and CNS graduate student Ronnie Bryan (PhD '12) to gather opinions on 36 photographs representing two different images of 18 individuals. One of each pair of images was taken at close range and the second at a distance of about seven feet.

"It turns out that faces photographed quite close-up are geometrically warped, compared to photos taken at a larger distance," explains Bryan. "Of course, the close picture would also normally be larger, higher resolution and have different lighting—but we controlled for all of that in our study. What you're left with is a warping effect that is so subtle that nobody in our study actually noticed it. Nonetheless, it's a perceptual clue that influenced their judgments."

That subtle distance warping, however, had a big effect: close-up photos made people look less trustworthy, according to study participants. The close-up photo subjects were also judged to look less attractive and competent.

"This was a surprising, and surprisingly reliable, effect," says Adolphs. "We went through a bunch of experiments, some testing people in the lab, and some even over the Internet; we asked participants to rate trustworthiness of faces, and in some experiments we asked them to invest real money in unfamiliar people whose faces they saw as a direct measure of how much they trusted them."

Across all of the studies, the researchers saw the same effect, Adolphs says: in photos taken from a distance of around two feet, a person looked untrustworthy, compared to photos taken seven feet away. These two distances were chosen by the researchers because one is within, and the other outside of, personal space—which on average is about three to four feet from the body.

In some of the studies, the researchers digitally warped images of faces taken at a distance to artificially manipulate how trustworthy they would appear. "Once you know the relation between the distance warp and the trustworthiness judgment, you could manipulate photos of faces and change the perceived trustworthiness,'' notes Perona.

He says that the group is now planning to build on these findings, using machine-vision techniques—technologies that can automatically analyze data in images. For example, one application would be for a computer program to have the ability to evaluate any face image in a magazine or on the Internet and to estimate the distance at which the photo was taken.

"The work might also allow us to estimate the perceived trustworthiness of a particular face image," says Perona. "You could imagine that many people would be interested in such applications—particularly in the political arena."

The study, "Perspective Distortion from Interpersonal Distance Is an Implicit Visual Cue for Social Judgments of Faces," was funded by grants from the National Institute of Mental Health and from the Gordon and Betty Moore Foundation.

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When Judging Portraits, Distance Matters
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Moving Targets

Caltech Biologists Gain New Insight into Migrating Cells

PASADENA, Calif.—At any given moment, millions of cells are on the move in the human body, typically on their way to aid in immune response, make repairs, or provide some other benefit to the structures around them. When the migration process goes wrong, however, the results can include tumor formation and metastatic cancer. Little has been known about how cell migration actually works, but now, with the help of some tiny worms, researchers at the California Institute of Technology (Caltech) have gained new insight into this highly complex task.

The team's findings are outlined this week online in the early edition of the Proceedings of the National Academy of Sciences (PNAS).

"In terms of cancer, we know how to find primary tumors and we know when they're metastatic, but we're missing information on the period in between when cells are crawling around, hanging out, and doing who knows what that leads to both of these types of diseases," says Paul Sternberg, Thomas Hunt Morgan Professor of Biology at Caltech, and corresponding author of the paper.

To learn more about those crawling, or migrating, cells, Sternberg looked at the animal he knows best—the tiny Caenorhabditis elegans, a common species of roundworm that he has been studying for many years. Despite their small size, the worms actually share quite a few genes with humans. 

"Migration is such a conserved process," says Mihoko Kato, a senior research fellow in biology at Caltech and a coauthor of the paper. "So whether it happens in C. elegans or in mammals, like humans, we think that many of the same genes are going to be involved."

Contained in each cell—be it human or worm—are thousands of genes, all of which have a special job, or jobs, to do. Of these genes, roughly one-third are active in a given cell. To see what genes are expressed during migration, Sternberg and Kato, along with Erich Schwarz, a research fellow in Sternberg's lab, studied a single cell, called the linker cell (LC), in the worms; during reproductive development, LCs travel almost the entire length of the worm's body.

Using high-powered microscopy, the team identified LCs at two intervals, 12 hours apart, during the worm's larval stage, and removed them from the animals. Then, using sequencing and computational analysis, they determined the genes that were actively expressed at these two migration time points. This method of study is called transcriptional profiling.

"By understanding the normal migration of a single cell, we can understand something about how the cells are programmed to navigate their environment," says Sternberg, who is also an investigator with the Howard Hughes Medical Institute. "Our view of cancer metastasis is that the tumor cells confront some obstacle and then they have to evolve to get through or around that obstacle. The way they probably do that is by using some aspect of the normal program that exists somewhere in the genome."

He says that learning more about different ways that cells migrate may lead to the development of new types of drugs that block this process by targeting specific genes. The team plans additional transcriptional profiling studies to obtain more detailed information about the functions of particular C. elegans genes involved in migration—and, eventually, of similar genes in higher organisms, including humans.

"We selected genes present in both worms and humans, but which have not been studied much before us," says Schwarz.  "Since we found that some of these genes help worm LCs migrate, we think each one may have a related human gene helping cells migrate, too."

"The nice thing about this technology is that you can use it with any cell type," adds Kato, who points out that their studies have already helped identify new functions for known genes possessed by both the worms and humans. "It's a similar process to do transcriptome profiling using human cells."

In addition to identifying drug targets, the team is also hoping to find a good signature, or molecular marker, for migrating cells. "This kind of information could be very useful diagnostically, to help identify cells that are doing things that they shouldn't be doing, or weird combinations of genes that shouldn't be expressed together, which is what a tumor cell might have," says Sternberg. "This work lays the foundation for really understanding what information is critically needed from mammalian cells for tumor cells to be able to migrate."

The study, "Functional transcriptomics of a migrating cell in Caenorhabditis elegans," was funded by the National Institutes of Health and the Howard Hughes Medical Institute.

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Moving Targets: Migrating Cells
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Two Caltech Researchers Receive NIH Director's Awards

Two members of the California Institute of Technology (Caltech) faculty have been given National Institutes of Health (NIH) Director's Awards. The awards are administered through the NIH's Common Fund, which provides support for research deemed to be both innovative and risky.

"The Common Fund High Risk–High Reward program provides opportunities for innovative investigators in any area of health research to take risks when the potential impact in biomedical and behavioral science is high," said NIH Director Francis S. Collins in a press release.

There are three types of NIH Director's Awards: the Pioneer Award, the New Innovator Award, and the Transformative Research Award. This year, biologist Doris Ying Tsao was given one of 10 Pioneer Awards, and geobiologist Dianne K. Newman was among the 20 scientists to receive Transformative Research Awards.

The Pioneer Award, established in 2004, "challenges investigators at all career levels to develop highly innovative approaches that have the potential to produce a high impact on a broad area of biomedical or behavioral research," according to the NIH. Tsao, an assistant professor of biology, will explore the question of how objects that we see are initially processed in the brain. 

"The retina essentially transmits an array of unconnected pixels to the brain. These are first processed locally, through various local filters for color, motion, etc., and the image does not yet contain objects, or bound units," says Tsao. "But after this, there is a mysterious operation that puts all these local pieces together for the first time—and that is what I am studying. I want to know how the brain dynamically links all these pixels over space and time, based on surface contiguity, to form bound units."

For example, as a truck makes a U-turn, the pixels defining the truck can change completely, yet we have no trouble tracking those pixels and seeing they belong to a single invariant object, she explains. 

"I am incredibly excited to have the chance, with the NIH Pioneer Award, to hunt for the circuits implementing these computations within the brain," says Tsao. "We just have to open our eyes to know the circuits exist, but understanding them is going to be an immense challenge that will require huge resources, and to now suddenly have these resources is unbelievable to me." 

The Transformative Research Award program, established in 2009, "promotes cross-cutting, interdisciplinary approaches" for research that "has the potential to create or overturn fundamental paradigms," according to the NIH. Newman, professor of biology and geobiology, will use the award to apply geobiological approaches to understanding the progression of pulmonary infections. 

Due to the challenges of working in situ, or in the body, most studies of infectious disease agents are conventionally performed with representative isolates and imperfect disease models in the laboratory, says Newman. Very few direct measurements of the physiological state of drug-tolerant populations in the host exist, and little is known about which metabolic pathways are actually in play, much less how they change over time in response to coevolving conditions within the lung, she explains. 

"We will tackle this critical knowledge gap using an approach inspired by geobiology," says Newman, who is also an investigator with the Howard Hughes Medical Institute. "Geobiologists are experienced in studying the growth and metabolism of microbial populations in poorly accessible natural habitats by combining molecular biology and stable isotope geochemistry; we will apply these tools to the lung." 

The goal of this project, she says, is to lay a foundation for novel therapeutics to modify and control infectious disease agents. 

"I am honored to have received this award because it will take our research in a meaningful new direction," says Newman. "The opportunity to collaborate with an outstanding group of colleagues at Caltech and at USC and Johns Hopkins hospitals is very exciting. I'm grateful that the NIH took a chance on our idea, and I hope it fulfills its promise."

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Researchers Receive NIH Director's Awards
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Modeling the Genes for Development

Caltech biologists create the first predictive computational model of gene networks that control the development of sea-urchin embryos

PASADENA, Calif.—As an animal develops from an embryo, its cells take diverse paths, eventually forming different body parts—muscles, bones, heart. In order for each cell to know what to do during development, it follows a genetic blueprint, which consists of complex webs of interacting genes called gene regulatory networks.

Biologists at the California Institute of Technology (Caltech) have spent the last decade or so detailing how these gene networks control development in sea-urchin embryos. Now, for the first time, they have built a computational model of one of these networks.

This model, the scientists say, does a remarkably good job of calculating what these networks do to control the fates of different cells in the early stages of sea-urchin development—confirming that the interactions among a few dozen genes suffice to tell an embryo how to start the development of different body parts in their respective spatial locations. The model is also a powerful tool for understanding gene regulatory networks in a way not previously possible, allowing scientists to better study the genetic bases of both development and evolution.

"We have never had the opportunity to explore the significance of these networks before," says Eric Davidson, the Norman Chandler Professor of Cell Biology at Caltech. "The results are amazing to us."

The researchers described their computer model in a paper in the Proceedings of the National Academy of Sciences that appeared as an advance online publication on August 27.

The model encompasses the gene regulatory network that controls the first 30 hours of the development of endomesoderm cells, which eventually form the embryo's gut, skeleton, muscles, and immune system. This network—so far the most extensively analyzed developmental gene regulatory network of any animal organism—consists of about 50 regulatory genes that turn one another on and off.

To create the model, the researchers distilled everything they knew about the network into a series of logical statements that a computer could understand. "We translated all of our biological knowledge into very simple Boolean statements," explains Isabelle Peter, a senior research fellow and the first author of the paper. In other words, the researchers represented the network as a series of if-then statements that determine whether certain genes in different cells are on or off (i.e., if gene A is on, then genes B and C will turn off).

By computing the results of each sequence hour by hour, the model determines when and where in the embryo each gene is on and off. Comparing the computed results with experiments, the researchers found that the model reproduced the data almost exactly. "It works surprisingly well," Peter says.

Some details about the network may still be uncovered, the researchers say, but the fact that the model mirrors a real embryo so well shows that biologists have indeed identified almost all of the genes that are necessary to control these particular developmental processes. The model is accurate enough that the researchers can tweak specific parts—for example, suppress a particular gene—and get computed results that match those of previous experiments.

Allowing biologists to do these kinds of virtual experiments is precisely how computer models can be powerful tools, Peter says. Gene regulatory networks are so complex that it is almost impossible for a person to fully understand the role of each gene without the help of a computational model, which can reveal how the networks function in unprecedented detail.

Studying gene regulatory networks with models may also offer new insights into the evolutionary origins of species. By comparing the gene regulatory networks of different species, biologists can probe how they branched off from common ancestors at the genetic level.

So far, the researchers have only modeled one gene regulatory network, but their goal is to model the networks responsible for every part of a sea-urchin embryo, to build a model that covers not just the first 30 hours of a sea urchin's life but its entire embryonic development. Now that this modeling approach has been proven effective, Davidson says, creating a complete model is just a matter of time, effort, and resources. 

The title of the PNAS paper is "Predictive computation of genomic logic processing functions in embryonic development." In addition to Peter and Davidson, the other author on the PNAS paper is Emmanuel Faure, a former Caltech postdoctoral scholar who is now at the École Polytechnique in France. This work was supported by the National Institute of Child Health and Human Development and the National Institute of General Medical Sciences.

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Caltech Researchers Find Evidence of Link between Immune Irregularities and Autism

PASADENA, Calif.—Scientists at the California Institute of Technology (Caltech) pioneered the study of the link between irregularities in the immune system and neurodevelopmental disorders such as autism a decade ago. Since then, studies of postmortem brains and of individuals with autism, as well as epidemiological studies, have supported the correlation between alterations in the immune system and autism spectrum disorder.

What has remained unanswered, however, is whether the immune changes play a causative role in the development of the disease or are merely a side effect. Now a new Caltech study suggests that specific changes in an overactive immune system can indeed contribute to autism-like behaviors in mice, and that in some cases, this activation can be related to what a developing fetus experiences in the womb.

The results appear in a paper this week in the Proceedings of the National Academy of Sciences (PNAS).

"We have long suspected that the immune system plays a role in the development of autism spectrum disorder," says Paul Patterson, the Anne P. and Benjamin F. Biaggini Professor of Biological Sciences at Caltech, who led the work. "In our studies of a mouse model based on an environmental risk factor for autism, we find that the immune system of the mother is a key factor in the eventual abnormal behaviors in the offspring."

The first step in the work was establishing a mouse model that tied the autism-related behaviors together with immune changes. Several large epidemiological studies—including one that involved tracking the medical history of every person born in Denmark between 1980 and 2005—have found a correlation between viral infection during the first trimester of a mother's pregnancy and a higher risk for autism spectrum disorder in her child. To model this in mice, the researchers injected pregnant mothers with a viral mimic that triggered the same type of immune response a viral infection would.

"In mice, this single insult to the mother translates into autism-related behavioral abnormalities and neuropathologies in the offspring," says Elaine Hsiao, a graduate student in Patterson's lab and lead author of the PNAS paper. 

The team found that the offspring exhibit the core behavioral symptoms associated with autism spectrum disorder—repetitive or stereotyped behaviors, decreased social interactions, and impaired communication. In mice, this translates to such behaviors as compulsively burying marbles placed in their cage, excessively self grooming, choosing to spend time alone or with a toy rather than interacting with a new mouse, or vocalizing ultrasonically less often or in an altered way compared to typical mice. 

Next, the researchers characterized the immune system of the offspring of mothers that had been infected and found that the offspring display a number of immune changes. Some of those changes parallel those seen in people with autism, including decreased levels of regulatory T cells, which play a key role in suppressing the immune response. Taken together, the observed immune alterations add up to an immune system in overdrive—one that promotes inflammation.

"Remarkably, we saw these immune abnormalities in both young and adult offspring of immune-activated mothers," Hsiao says. "This tells us that a prenatal challenge can result in long-term consequences for health and development."

With the mouse model established, the group was then able to test whether the offspring's immune problems contribute to their autism-related behaviors. In the most revealing test of this hypothesis, the researchers were able to correct many of the autism-like behaviors in the offspring of immune-activated mothers by giving the offspring a bone-marrow transplant from typical mice. The normal stem cells in the transplanted bone marrow not only replenished the immune system of the host animals but altered their autism-like behavioral impairments. 

The researchers emphasize that because the work was conducted in mice, the results cannot be readily extrapolated to humans, and they certainly do not suggest that bone-marrow transplants should be considered as a treatment for autism. They also have yet to establish whether it was the infusion of stem cells or the bone-marrow transplant procedure itself—complete with irradiation—that corrected the behaviors.

However, Patterson says, the results do suggest that immune irregularities in children could be an important target for innovative immune manipulations in addressing the behaviors associated with autism spectrum disorder. By correcting these immune problems, he says, it might be possible to ameliorate some of the classic developmental delays seen in autism.

In future studies, the researchers plan to examine the effects of highly targeted anti-inflammatory treatments on mice that display autism-related behaviors and immune changes. They are also interested in considering the gastrointestinal (GI) bacteria, or microbiota, of such mice. Coauthor Sarkis Mazmanian, a professor of biology at Caltech, has shown that gut bacteria are intimately tied to the function of the immune system. He and Patterson are investigating whether changes to the microbiota of these mice might also influence their autism-related behaviors.

Along with Patterson, Hsiao, and Mazmanian, additional Caltech coauthors on the PNAS paper, "Modeling an autism risk factor in mice leads to permanent immune dysregulation," are Mazmanian lab manager Sara McBride and former graduate student Janet Chow. The work was supported by an Autism Speaks Weatherstone Fellowship, National Institutes of Health Graduate Training Grants, a Weston Havens Foundation grant, a Gregory O. and Jennifer W. Johnson Caltech Innovation Fellowship, a Caltech Innovation grant, and a Congressionally Directed Medical Research Program Idea Development Award. 

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Kimm Fesenmaier
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Autism and the Immune System
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Caltech Receives Gift from Sackler Foundation to Advance Biomedical Science Research

PASADENA, Calif.—The California Institute of Technology (Caltech) and UCLA have launched highly productive collaborations in cancer research and other areas of biomedicine in recent years, frequently through the Caltech lab of Nobel Laureate and President Emeritus David Baltimore. Now, an endowment established by the Raymond and Beverly Sackler Foundation will strengthen the Caltech-UCLA partnership and advance the Baltimore lab's interdisciplinary research into areas where mathematics and engineering converge with biology.

The Sackler endowment will support three primary areas: postdoctoral researchers working in areas that have a convergent theme; students pursuing a joint MD/PhD degree through the Caltech-UCLA Medical Scientist Training Program; and a joint seminar series between Caltech and UCLA emphasizing the interface of medicine, engineering, and the physical sciences.

"Caltech has a strong interdisciplinary focus that is fueling its outstanding achievements in biomedical research," says Caltech's president Jean-Lou Chameau. "The support from the Raymond and Beverly Sackler Foundation further enhances this research, which can lead to therapies for some of the world's most critical diseases."

The research supported by the endowment will encompass many of the numerous disciplines that have become intertwined with biology in recent years, such as computational mathematics and physics. There is also an important educational component, as the Sackler endowment will help train MD/PhD students and strengthen the link between Caltech's basic science expertise and UCLA's translational medicine focus.

"The Sackler gift is very important because it allows us to expand our research in a direction in which I very much want it to go, and at the same time it will support our very significant MD/PhD program," says Baltimore, the Robert Andrews Millikan Professor of Biology. "We are grateful to Raymond and Beverly Sackler for their generosity and for their foresight in recognizing the importance of our work."

Dr. Raymond Sackler is a physician, entrepreneur, and philanthropist who has supported numerous scientific and cultural initiatives throughout the world. With his late brothers, Arthur and Mortimer, he sponsored the Sackler Faculty of Medicine, and with his wife, Beverly, has sponsored the Raymond and Beverly Sackler Faculty of Exact Sciences, both at Tel Aviv University. David Baltimore and Caltech are one of 10 recipients of endowments from the foundation as part of a recent global program in support of convergent research.

"The purpose of this gift is to catalyze new convergent science investigations and to honor the important research that has been carried out by David Baltimore," says Raymond Sackler. "He made groundbreaking scientific accomplishments at a relatively early age, and now—working at the crossroads of several disciplines—he continues to make major discoveries in biomedical research. We hope that this new endowment will foster his research and Caltech's dynamic collaborations with UCLA."

Baltimore is best known for his work with viruses and the immune system, and he shared the Nobel Prize in Physiology or Medicine in 1975 for his discoveries concerning cancer-inducing viruses. Several years ago, he decided that his research should move toward translational applications, and in 2009 he became the director of a new effort with UCLA—the Joint Center for Translational Medicine—which supports numerous research projects with the potential for clinical applications.

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Michael Rogers
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