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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Focusing on Faces

Researchers find neurons in amygdala of autistic individuals have reduced sensitivity to eye region of others' faces

Difficulties in social interaction are considered to be one of the behavioral hallmarks of autism spectrum disorders (ASDs). Previous studies have shown these difficulties to be related to differences in how the brains of autistic individuals process sensory information about faces. Now, a group of researchers led by California Institute of Technology (Caltech) neuroscientist Ralph Adolphs has made the first recordings of the firings of single neurons in the brains of autistic individuals, and has found specific neurons in a region called the amygdala that show reduced processing of the eye region of faces. Furthermore, the study found that these same neurons responded more to mouths than did the neurons seen in the control-group individuals.

"We found that single brain cells in the amygdala of people with autism respond differently to faces in a way that explains many prior behavioral observations," says Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and coauthor of a study in the November 20 issue of Neuron that outlines the team's findings. "We believe this shows that abnormal functioning in the amygdala is a reason that people with autism process faces abnormally."

The amygdala has long been known to be important for the processing of emotional reactions. To make recordings from this part of the brain, Adolphs and lead author Ueli Rutishauser, assistant professor in the departments of neurosurgery and neurology at Cedars-Sinai Medical Center and visiting associate in biology at Caltech, teamed up with Adam Mamelak, professor of neurosurgery and director of functional neurosurgery at Cedars-Sinai, and neurosurgeon Ian Ross at Huntington Memorial Hospital in Pasadena, California, to recruit patients with epilepsy who had electrodes implanted in their medial temporal lobes—the area of the brain where the amygdala is located—to help identify the origin of their seizures. Epileptic seizures are caused by a burst of abnormal electric activity in the brain, which the electrodes are designed to detect. It turns out that epilepsy and ASD sometimes go together, and so the researchers were able to identify two of the epilepsy patients who also had a diagnosis of ASD.

By using the implanted electrodes to record the firings of individual neurons, the researchers were able to observe activity as participants looked at images of different facial regions, and then correlate the neuronal responses with the pictures. In the control group of epilepsy patients without autism, the neurons responded most strongly to the eye region of the face, whereas in the two ASD patients, the neurons responded most strongly to the mouth region. Moreover, the effect was present in only a specific subset of the neurons. In contrast, a different set of neurons showed the same response in both groups when whole faces were shown.

"It was surprising to find such clear abnormalities at the level of single cells," explains Rutishauser. "We, like many others, had thought that the neurological abnormalities that contribute to autism were spread throughout the brain, and that it would be difficult to find highly specific correlates. Not only did we find highly specific abnormalities in single-cell responses, but only a certain subset of cells responded that way, while another set showed typical responses to faces. This specificity of these cell populations was surprising and is, in a way, very good news, because it suggests the existence of specific mechanisms for autism that we can potentially trace back to their genetic and environmental causes, and that one could imagine manipulating for targeted treatment."

"We can now ask how these cells change their responses with treatments, how they correspond to similar cell populations in animal models of autism, and what genes this particular population of cells expresses," adds Adolphs.

To validate their results, the researchers hope to identify and test additional subjects, which is a challenge because it is very hard to find people with autism who also have epilepsy and who have been implanted with electrodes in the amygdala for single-cell recordings, says Adolphs.

"At the same time, we should think about how to change the responses of these neurons, and see if those modifications correlate with behavioral changes," he says.

Funding for the research outlined in the Neuron paper, titled "Single-neuron correlates of abnormal face processing in autism," was provided by the Simons Foundation, the Gordon and Betty Moore Foundation, the Cedars-Sinai Medical Center, Autism Speaks, and the National Institute of Mental Health. Additional coauthors were Caltech postdoctoral scholar Oana Tudusciuc and graduate student Shuo Wang.

Katie Neith
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New Department of Medical Engineering Added by the Caltech Division of Engineering and Applied Science

Caltech's Division of Engineering and Applied Science (EAS) has added a new department to its roster: the Department of Medical Engineering (MedE). MedE joins EAS's existing departments of Aerospace; Applied Physics and Materials Science; Computing and Mathematical Sciences; Electrical Engineering; Environmental Science and Engineering; and Mechanical and Civil Engineering. Like these other departments, MedE pulls together faculty from a broad range of specialties, both within EAS and outside it, to create an interdisciplinary program that aims to aid collaboration and provide graduate education in a critical area of engineering that directly and positively impacts human health and well-being.

MedE was formed to take advantage of Caltech's commitment to basic science, using this focus as a stepping-stone to finding fresh avenues to developing diagnostic tools, medical devices, and treatment options, in an approach sometimes known as translational, or "bench-to-bedside," medicine. Ares Rosakis, Theodore von Kármán Professor of Aeronautics and Mechanical Engineering and Booth Leadership Chair of the EAS division, explains that the MedE department was formed "in response to the desire of many of our faculty and of local research hospitals and medical foundations to engage jointly in engineering-centric technology development efforts for medical applications." To that end, the MedE department is already partnering with the Keck School of Medicine of USC, UCLA's Geffen School of Medicine, City of Hope, the UCSF School of Medicine, and Huntington Memorial Hospital, among others.

Combined with the newly established Division of Biology and Biological Engineering at Caltech, MedE positions Caltech to become an even more dynamic force in the field of bioengineering. As Vice Provost and Hans W. Liepmann Professor of Aeronautics and Bioinspired Engineering Morteza Gharib explains, "Medical engineering is top-down. We look at the problems that are currently challenging to the field and try to come up with devices and techniques to help clinicians do their job better or make breakthroughs. Biological engineering is bottom-up. It tries to understand how biology works and then builds upon that to get to the point where it can contribute to the field. Basically we're looking at the same wall from two different sides." Bringing the two sides together, says Gharib, "will not only help coordinate scientific work at Caltech but will also give outsiders a more accurate impression of how we at Caltech are taking a multifaceted approach to the challenges of bioengineering across disciplines."

"Caltech really has an opportunity here," says Yu-Chong Tai, Anna L. Rosen Professor of Electrical Engineering and Mechanical Engineering and executive officer of the new MedE department. "There are more than 60 accredited biomedical engineering programs in the United States, and there are about 100 biomedical programs at various universities and institutes. A lot of the work we want to do has to rely on deep engineering, which is our strength at Caltech. That's why our intention is to build the Caltech medical engineering department in a way that is rooted in really first-class engineering, moving from that base toward medical applications."

The expertise the MedE faculty bring to the department is deep and varied. In the field of diagnostics, Tai's research uses microelectromechanical and nanoelectromechanical systems (MEMS/NEMS) technologies to produce high-performance liquid chromatography (HPLC) on a chip and blood labs on a chip. Similar technologies are deployed for therapeutic treatments, such as the creation of miniature or micro implant devices including spinal neural stimulators, ECG implants, retinal prosthetic devices, intraocular lenses, and increasingly precise drug delivery systems. Gharib is looking into the use of nanoscale carbon-tube medical adhesives and painless nanoscale needles, and is also exploring the hemodynamics and wave dynamics of large blood vessels and embryonic heart flow with an eye toward cardiovascular medical applications. Joel Burdick, Richard L. and Dorothy M. Hayman Professor of Mechanical Engineering and Bioengineering, has been focusing his expertise in robotics to help patients suffering from paralysis. He and his colleagues have developed a rehabilitation technology that could lead to the successful repair of paralyzing spinal-cord injuries. Azita Emami, Professor of Electrical Engineering, and her team are designing high-performance, low-power, minimally invasive implantable and wearable medical devices for neural recording, neural stimulation, and drug delivery.

The medical engineering department is currently offering MS and PhD degrees, seeking to train a new generation of engineers to close the gap between engineering and medicine. The MedE department will cooperate with existing research centers at Caltech such as the Donna and Benjamin M. Rosen Bioengineering Center and the Center for Bioinspired Engineering. To learn more about the MedE department, visit its website at, or read an overview of the department's faculty and their ambitions for the new MedE program in the Fall 2013 issue of EAS's ENGenious magazine (

Cynthia Eller
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New Department of Medical Engineering Added
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Caltech Names Thomas F. Rosenbaum as New President

To: The Caltech Community

From: Fiona Harrison, Benjamin M. Rosen Professor of Physics and Astronomy, and Chair, Faculty Search Committee; and David Lee, Chair, Board of Trustees, and Chair, Trustee Selection Committee

Today it is our great privilege to announce the appointment of Thomas F. Rosenbaum as the ninth president of the California Institute of Technology.

Dr. Rosenbaum, 58, is currently the John T. Wilson Distinguished Service Professor of Physics at the University of Chicago, where he has served as the university's provost for the past seven years. As a distinguished physicist and expert on condensed matter physics, Dr. Rosenbaum has explored the quantum mechanical nature of materials, making major contributions to the understanding of matter near absolute zero, where such quantum mechanical effects dominate. His experiments in quantum phase transitions in matter are recognized as having played a key role in placing these transitions on a theoretical level equivalent to that which has been developed for classical systems.

But Dr. Rosenbaum's scientific achievements were not solely what captured and held the attention of those involved in the presidential search. We on the search committee were impressed by Dr. Rosenbaum's deep dedication, as Chicago's provost, to both undergraduate and graduate education—both critical parts of Caltech's mission. He has had responsibility for an unusually broad range of institutions and intellectual endeavors. Among his achievements as provost was the establishment of the Institute for Molecular Engineering in 2011, the University of Chicago's very first engineering program, in collaboration with Argonne National Lab.

We also believe that Dr. Rosenbaum's focus on strengthening the intellectual ties between the University of Chicago and Argonne National Lab will serve him well in furthering the Caltech-JPL relationship.

As provost, Dr. Rosenbaum was also instrumental in establishing collaborative educational programs serving communities around Chicago's Hyde Park campus, including the university's founding of a four-campus charter school that was originally designed to further fundamental research in education but which has also achieved extraordinary college placement results for disadvantaged Chicago youths.

This successful conclusion to our eight-month presidential search was result of the hard work of the nine-member Faculty Search Committee, chaired by Fiona Harrison, and the 10-member Trustee Selection Committee, chaired by David Lee. We are grateful both to the trustees and faculty on our two committees who made our job so very easy as well as to those faculty, students, staff, and alumni who provided us with input and wisdom as we scoured the country for just the right person for our Caltech.

"Tom embodies all the qualities the faculty committee hoped to find in our next president," Harrison says. "He is a first-rate scholar and someone who understands at a deep level the commitment to fundamental inquiry that characterizes Caltech. He is also the kind of ambitious leader who will develop the faculty's ideas into the sorts of innovative ventures that will maintain Caltech's position of prominence in the next generation of science and technology."

"The combination of deep management experience and visionary leadership Tom brings will serve Caltech extremely well in the coming years," Lee adds. "The Board is excited about collaborating closely with Tom to propel the Institute to new levels of scientific leadership."

"The Caltech community's palpable and deep commitment to the Institute came through in all my conversations, and it forms the basis for Caltech's and JPL's lasting impact," Dr. Rosenbaum says. "It will be a privilege to work closely with faculty, students, staff, and trustees to explore new opportunities, building on Caltech's storied accomplishments."

Dr. Rosenbaum received his bachelor's degree in physics with honors from Harvard University in 1977, and both an MA and PhD in physics from Princeton University in 1979 and 1982, respectively. He did research at Bell Laboratories and at IBM Watson Research Center before joining the University of Chicago's faculty in 1983. Dr. Rosenbaum directed the university's Materials Research Laboratory from 1991 to 1994 and its interdisciplinary James Franck Institute from 1995 to 2001 before serving as vice president for research and for Argonne National Laboratory from 2002 to 2006. He was named the university's provost in 2007. His honors include an Alfred P. Sloan Research Fellowship, a Presidential Young Investigator Award, and the William McMillan Award for "outstanding contributions to condensed matter physics." Dr. Rosenbaum is an elected fellow of the American Physical Society, the American Association for the Advancement of Science, and the American Academy of Arts and Sciences.

Joining the Caltech faculty will be Dr. Rosenbaum's spouse, Katherine T. Faber, the Walter P. Murphy Professor of Materials Science and Engineering at Northwestern University. Dr. Faber's research focuses on understanding stress fractures in ceramics, as well as on the fabrication of ceramic materials with controlled porosity, which are important as thermal and environmental barrier coatings for engine components. Dr. Faber is also the codirector of the Northwestern University-Art Institute of Chicago Center for Scientific Studies in the Arts (NU-ACCESS), which employs advanced materials science techniques for art history and restoration. Dr. Rosenbaum and Dr. Faber have two sons, Daniel, who graduated from the University of Chicago in 2012, and Michael, who is currently a junior there.

Dr. Rosenbaum will succeed Jean-Lou Chameau, who served the Institute from 2006 to 2013, and will take over the helm from interim president and provost Ed Stolper on July 1, 2014. The board, the search committee, and, indeed, the entire Institute owes Dr. Stolper a debt of gratitude for his unwavering commitment to Caltech, and for seamlessly continuing the Institute's forward momentum through his interim presidency.

As you meet Dr. Rosenbaum today and over the coming months, and learn more about his vision for Caltech's future, we believe that you will quickly come to see why he is so well suited to guide Caltech as we continue to pursue bold investigations in science and engineering, to ready the next generation of scientific and thought leaders, and to benefit humankind through research that is integrated with education.

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Programming DNA for Molecular Robots: An Interview with Lulu Qian

Embracing the idea that molecules can be programmed much like a computer, researchers can now perform remarkable feats on a very small scale. New Caltech faculty member Lulu Qian, assistant professor of bioengineering, performs research in the field of molecular programming because it allows her to design synthetic molecular systems with neural-network-like behaviors and tiny robots, both from the programmed interactions of DNA molecules. Originally from Nanjing, China, Qian received her bachelor's degree from Southeast University in 2002 and her PhD from Shanghai Jiao Tong University in 2007. After working as a postdoctoral scholar at Caltech in the laboratory of Shuki Bruck, Qian became a visiting fellow at Harvard University; she returned to Caltech and joined the faculty in July. Recently, Qian answered a few questions about her research, and how it feels to be back at Caltech.

What do you work on?

I work on rationally designing and creating molecular systems with programmable behaviors. I am interested in programming biological molecules—like DNA and RNA—to recognize molecular events from the biochemical environment, process information, make decisions, take actions, and to learn and evolve. Molecular programming is not just about using computer programs to aid the design and analysis of molecular systems; it is more about adapting the principles of computer science to create biochemical systems that can carry out instructions to perform tasks at the molecular level. For example, I develop simple and standard molecular components that can be used to perform a variety of tasks and systematic ways to configure the behavior of interacting molecules to carry out one computational or mechanical task or another. These custom-designed molecules can be ordered from a commercial supplier and mixed in a test tube to generate a "molecular program." 

Using this approach, I have designed DNA circuits that can solve basic logic problems, and I have constructed a DNA neural network that can perform simple associative memory functions—much like a network of neurons in the brain, though in a rudimentary way. In my future research, I would like to improve the speed, robustness, and complexity of these implementations and to explore the possibility of creating molecular systems with learning capabilities, while also beginning new work in the field of molecular robots—tiny, nanoscale machines made of DNA that can perform a designed task such as sorting cargo or solving a maze.

What do you find most exciting about your research?

I am driven by curiosity—outside of the lab, I like Legos and puzzles—and I view life as a program, one that is much more sophisticated than any other program that we know of so far. The sequence of nucleotides that make up DNA—As, Ts, Cs, and Gs—encodes the program within a genome, orchestrating molecules to sense, to compute, to respond, and to grow. Because of their different lengths and sequences, one genome produces a bacterium while another produces a plant, or an insect, or a mammal. The genetic program describes how to make molecules, and molecules are machines that can achieve complex tasks to regulate the behaviors of individual cells. To better appreciate the molecular programs that nature creates, I want to understand what possible behaviors a network of interacting molecules can exhibit and how we can rationally design such behaviors.

But, I am also driven by my engineering nature. I want to design and build molecular systems with increasing complexity and sophistication. For example, you could imagine using such molecular machines to make a nanoscale factory that manufactures novel chemicals in a test tube. These chemicals could become new materials or new drugs. You could also imagine embedding such molecular machines into individual cells so that you could collect information from the molecular environment and regulate the cell's behavior. Such regulation could lead to responsive biosynthesis—the production of proteins or other molecules in response to a stimulus—or localized diagnostics followed by therapeutics.

How did you get into your field?

I started programming computers when I was 13 years old, and I have loved it ever since then. My dad was a philosopher, and because of his influence, I got curious about fundamental questions such as who I am and why I think the way that I do. At first, I tried to look for these answers in molecular biology, but as a programmer, biology was difficult for me to understand. Unlike in programming, you cannot just define a few logical principles to understand the behavior of an entire biological system or organism. At the time, biology was not as fun for me—or as logical—as computer programming.

But just before I went to graduate school, I discovered the first publication in DNA computing by Len Adleman at the University of Southern California. He used DNA molecules as a computing substrate to solve a hard math problem. The moment that I finished reading this paper, I felt completely excited. It was the first time that I saw a strong relationship between molecules that are traditionally only used in biology—like DNA and RNA—and computer programming. That was when I started working in my field.   

Why are you excited to be at Caltech?

After working at other institutions, Caltech has been a very special place for me. I like that Caltech is small and is an environment in which we're encouraged to pursue fundamental research and appreciate the beauty of science. I am most excited about doing great science here. There are very talented students—I am looking for the most fun and creative minds to join my lab—and I have visionary colleagues. We have an excellent molecular programming community at Caltech, including Erik Winfree in computer science, Shuki Bruck in electrical engineering, Richard Murray in control and dynamical systems, Niles Pierce and Paul Rothemund in bioengineering, and now myself. And we now have this new division, Biology and Biological Engineering, which I believe will bring fundamental engineering to biological sciences and create interdisciplinary research activities.

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Look Out Above! Experiment Explores Innate Visual Behavior in Mice

When you're a tiny mouse in the wild, spotting aerial predators—like hawks and owls—is essential to your survival. But once you see an owl, how is this visual cue processed into a behavior that helps you to avoid an attack? Using an experimental video technique, researchers at the California Institute of Technology (Caltech) have now developed a simple new stimulus with which they can spur the mouse's escape plans. This new stimulus allows the researchers to narrow down cell types in the retina that could aid in the detection of aerial predators.

"The mouse has recently become a very popular model for the study of vision," says biology graduate student Melis Yilmaz, who is also first author of the study, which will be published online in the journal Current Biology on October 10. "Our lab and other labs have done a lot of physiological, anatomical, and histological studies in the mouse retina"—a layer of light-sensitive cells in the eye that relay image information to the brain—"but the missing piece was mouse behavior: What do mice do with their vision?"

Yilmaz, under the supervision of Markus Meister, Lawrence A. Hanson, Jr. Professor of Biology, studied the behavior of 40 mice, placed one-by-one in a tiny room called a behavioral arena. After placing each mouse alone in the arena and letting it explore the new environment for a few minutes, Yilmaz played videos of different visual stimuli on a computer monitor mounted on the ceiling, the screen facing down onto the arena. The researchers then watched a video feed of the mouse's behavior, obtained with a camera located on one of the walls of the arena.

Surprisingly, all of the mice responded to one specific visual stimulus: an expanding black disk, which is meant to imitate the appearance of an approaching aerial predator.

A quarter of the mice responded to the looming disk by completely freezing in place, not moving a muscle or twitching a whisker or tail until the disk disappeared. "When I first saw this behavior, my first thought was that the video recording had stopped," Yilmaz says.

Example of mouse "freezing" upon viewing the looming disk stimulus above.

Example of mouse "freezing" upon viewing the looming disk stimulus above.
Example of mouse "freezing" upon viewing the looming disk stimulus above. Results of this study published in the paper "Rapid Innate Defensive Responses of Mice to Looming Visual Stimuli" on October 10, 2013 in Current Biology.
Credit: Melis Yilmaz and Markus Meister/California Institute of Technology


A far more common reaction to the looming disk—seen in around 75 percent of the mice—was to flee for the cover of a tent-like nest in one corner of the arena.

Example of mouse fleeing upon viewing the looming disk stimulus above.

Example of mouse fleeing upon viewing the looming disk stimulus above.
Example of mouse fleeing upon viewing the looming disk stimulus above. Results of this study published in the paper "Rapid Innate Defensive Responses of Mice to Looming Visual Stimuli" on October 10, 2013 in Current Biology.
Credit: Melis Yilmaz and Markus Meister/California Institute of Technology


"For each mouse, this was the very first time that the animal was put into this arena, and it was the very first time that it saw that stimulus, and yet it has this sort of immediate reflex-like response…beginning to flee in less than a quarter of a second," Meister says. "What's attractive about this behavior is that it's incredibly robust, so we can rely on it, and it's quite specific to this particular visual stimulus. If the same disk was presented on a monitor at the bottom of the arena, the animals don't respond to that at all. And a looming white disk is also much less effective," he adds.

Although their study wasn't designed to evaluate the purpose of the two responses, Yilmaz and Meister suspect that, in the wild, different environmental conditions could lead to different visual behaviors.

"If you were out in nature, maybe freezing is a good reaction to a predatory bird that is very far away because it would allow you to blend into the surroundings," Meister says. This would confound the bird's visual system, which uses movement to track targets. Furthermore, he adds, "If the bird is within hearing distance, freezing so completely would help it avoid making a rustling noise."

The behaviors these researchers observed in this experiment are not uncommon among other animals in the wild, as Meister discovered one evening after giving a presentation about the fleeing and freezing results. "When I came home that evening, my son said, 'Papi, you won't believe what happened when we were at the park today. This squirrel was running across a wall, and suddenly it just froze! And then some guy yelled, 'Hey look!' and there was a hawk circling around.' So he had just that day seen it in real life," Meister says.

Freezing might be the best game plan for an animal trying to avoid predators that are far away, but, Meister says, when the threat is closer "and there is a protective place nearby, then escape might be a better strategy."

When Yilmaz and Meister began connecting these specific behavioral observations with other information about the mouse visual system, they were able to make predictions about the types of neurons and circuits involved in this rapid response. "We tested four different speeds of the expanding disk video, and we found that only one of those speeds caused this behavior robustly," Meister says. "That also gives us clues about what types of cells in the retina might be involved, because we know that one type responds to high-speed motion and one type responds to low-speed motions. The cells that detect low-speed motion are probably not involved in this behavior."

"It's really striking to me to watch the animal completely ignore one stimulus—like an expanding white disk—whereas they have such a robust reaction to the other type of stimulus," Yilmaz says. Her next experiments will be focused on manipulating these candidate cell types to pinpoint exactly which types of neurons and circuits are involved in this visual behavior.

In addition to its specific implications for visual behaviors, the work also helps to validate the mouse model for the study of visual processing, Meister says. Mice used in research have been bred for dozens of generations in laboratories—where they never would have seen an aerial predator—and yet the instinctual behavior still exists. "Lab mice never had to learn that a dark object from above was bad news," he says. "In fact, in our experiments, there was never any kind of punishment or ill effect from a visual display, so they didn't have any chance to learn the meaning. We believe it's kind of built into their genetic constitution."

Although humans don't have to escape the threat of predatory birds, Meister says that the results from this research could eventually provide information about human visual behaviors. "The mouse and human retinas are really very similar, so many of the circuits that are important for the mouse have analogous circuits in the human retina," he says. "Humans also react instinctively to approaching objects, but, obviously, we don't freeze. So, how did nature change a circuit that helps one animal escape from predators so that it serves a different function in another animal?"

This work was published in a paper titled "Rapid Innate Defensive Responses of Mice to Looming Visual Stimuli." The research was funded by the National Institutes of Health.

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Minding the Gaps in the Genome: An Interview with Mitch Guttman

Mitchell Guttman is a new assistant professor of biology on campus. He just arrived last month, having recently completed a fellowship at the Broad Institute of MIT and Harvard. Originally from Brooklyn, New York, Guttman received both his BS and MS degrees in 2006 from the University of Pennsylvania and completed his PhD at MIT in 2012. Since then, he has received an NIH Early Independence Award and was included on Forbes magazine's 30 Under 30: Science and Healthcare list.

While still a graduate student at the Broad Institute, Guttman led the team that first described a special class of genes called lncRNAs (large noncoding RNAs, pronounced "link RNAs"). These pieces of genetic material fall between the genes that code for proteins, and therefore had been largely overlooked previously. However, researchers are now finding that these lncRNAs are important players in genome regulation and cellular organization. Guttman's lab at Caltech will continue to study lncRNAs—how they work, why they are needed, and what makes them special. A recent paper in Science Express shares the latest.

Guttman recently took a break from setting up his lab to answer a few questions.

Do you remember how you first became interested in science?

I've always kind of been interested in science, ever since high school. I had a really great chemistry teacher who recognized my love of chemistry and biology and introduced me to some researchers at Mount Sinai in New York. I started doing research there at the end of my sophomore year of high school and worked there through my senior year. It was cancer research—mostly looking at breast cancer, and migration and adhesion patterns. I was doing very basic molecular biology, and I learned a ton.

When I was an undergraduate at Penn, the person I had worked with back in high school introduced me to one of his colleagues—a pathologist at Penn who was starting to do a lot of work on cancer genomics, which I knew nothing about but which sounded very fascinating. I started working with her my freshman year. During that time, it became very clear to me that to understand this work, I had to delve into the quantitative and computational aspects. I eventually helped develop computational methods to look at cancer mutation patterns and identify the "driver" mutations in the cancer genome versus the passengers—things that just come along for the ride but don't really have a direct effect in causing cancer. At the time, there weren't any methods to do that.

When I started graduate school, I wanted to work on cancer. That's how I met Eric Lander, the director of the Broad Institute, who was my graduate advisor.

How did you end up working on lncRNAs?

At the time I joined Eric's lab, there was kind of a revolution going on in genomics. Next-generation sequencing—ultrahigh-throughput, massively parallel sequencing—was starting to come online. There were very few institutions in the world that had instruments to do this—the Broad was one, Caltech was one. These were the first instruments that allowed us to sequence DNA at unparalleled depth. Eric's lab was using these instruments to look at chromatin modifications—how DNA wraps around different proteins, or histones, in the nucleus—and they had all of this new data. It hadn't been published. So Eric said, "I bet there's something here to be found. You're a computational guy; why don't you play around with it?"

The first thing I did, as a good computational guy, was to try to figure out a good algorithm to make sense of it. Once I did, it kind of hit me in the face.

What did you find?

Until then, we hadn't been able to look at anything but genes. But when we were able to look at the whole genome, we saw all of these regions of intergenic space—things that were between genes—that looked like genes. They had chromatin modifications with patterns that looked identical to genes. That suggested that there were thousands of unannotated genes. What became clear immediately was that although they had the same patterns as protein-coding genes, they didn't code for proteins. They did not have evolutionary signatures that looked like proteins. They were very different. We called them lncRNAs.

That finding basically led me on what has now been a seven-year stretch of trying to figure out what they are, what they do, and how they work.

Had no one previously looked at histone modifications?

They had, but they were mostly looking at very specialized regions—they were looking at promoters, which are regions that control transcription, or they were looking at proteins, or they were looking at the genes themselves. But only 1 percent of the genome encodes proteins, so 99 percent is really a no-man's-land, if you will. There had been no methods to pick out and classify these patterns across the entire genome, because there had been no data.

We wrote a computer program to search for these regions. We never named the original program, but its successor was called Scripture.

Why was all of this so exciting?

It made me realize that there were in fact thousands of these large noncoding RNAs that looked like proteins but didn't act like proteins—they did something else. What that something else was, I didn't know, but it was new and unexplored and was clearly important. The potential was huge.

And as a scientist, you can't just turn away when you find something like this. You've got to figure it out. The idea was exciting: there were all these thousands of genes that had previously been missed and unappreciated that could play really important roles in ways that we didn't understand. I wanted to know how they work. What are they doing? We're still figuring it out. Every time we find something, it is more exciting than I would have anticipated. That's what I love about this: it's never been obvious; it's never been dull.

Why did you choose to come to Caltech?

Caltech's an amazing place. I love the faculty. I love the small size. I love how interactive and not overlapping but collaborative it is. No other place that I had been to was like this—this seamless—and in no place did I feel as comfortable talking with chemists and engineers as I did with biologists. The breadth of the institution and the vision and the interactions were pretty unique and exciting.

Kimm Fesenmaier
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Caltech Named World's Top University in Times Higher Education Global Ranking

For the third year in a row, the California Institute of Technology has been rated the world's number one university in the Times Higher Education global ranking of the top 200 universities.

Harvard University, Oxford University, Stanford University, and the Massachusetts Institute of Technology round out the top five schools in the 2013–2014 rankings.

Times Higher Education compiled the listing using the same methodology as in the 2011–2012 and 2012–2013 surveys. 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. The data were collected, analyzed, and verified by Thomson Reuters.

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

Kathy Svitil
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